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39487265 | 300 | Development of compact transcriptional effectors using high-throughput measurements in diverse contexts. | Transcriptional effectors are protein domains known to activate or repress gene expression; however, a systematic understanding of which effector domains regulate transcription across genomic, cell type and DNA-binding domain (DBD) contexts is lacking. Here we develop dCas9-mediated high-throughput recruitment (HT-recruit), a pooled screening method for quantifying effector function at endogenous target genes and test effector function for a library containing 5,092 nuclear protein Pfam domains across varied contexts. We also map context dependencies of effectors drawn from unannotated protein regions using a larger library tiling chromatin regulators and transcription factors. We find that many effectors depend on target and DBD contexts, such as HLH domains that can act as either activators or repressors. To enable efficient perturbations, we select context-robust domains, including ZNF705 KRAB, that improve CRISPRi tools to silence promoters and enhancers. We engineer a compact human activator called NFZ, by combining NCOA3, FOXO3 and ZNF473 domains, which enables efficient CRISPRa with better viral delivery and inducible control of chimeric antigen receptor T cells. | [
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"many effectors",
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"DBD contexts",
"unannotated protein regions",
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"5,092 nuclear protein Pfam domains",
"context-robust domains",
"better viral delivery",
"efficient CRISPRa",
"CRISPRi tools",
"efficient perturbations",
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"transcription factors",
"ZNF705 KRAB",
"chromatin regulators",
"transcription",
"target",
"NCOA3, FOXO3 and ZNF473 domains",
"NFZ",
"NCOA3"
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10.1038/nature12787 | [
"Tycko",
"Van",
"Aradhana",
"DelRosso",
"Ye",
"Yao",
"Valbuena",
"Vaughan-Jackson",
"Xu",
"Ludwig",
"Spees",
"Liu",
"Gu",
"Khare",
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] | [
"Department of Genetics, Stanford University, Stanford, CA, USA.\nDepartment of Neurobiology, Harvard Medical School, Boston, MA, USA.",
"Department of Biology, Stanford University, Stanford, CA, USA.",
"Department of Genetics, Stanford University, Stanford, CA, USA.",
"Biophysics Program, Stanford University, Stanford, CA, USA.",
"Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA, USA.",
"Department of Genetics, Stanford University, Stanford, CA, USA.",
"Department of Genetics, Stanford University, Stanford, CA, USA.",
"Department of Genetics, Stanford University, Stanford, CA, USA.\nChan Zuckerberg Biohub-San Francisco, San Francisco, CA, USA.",
"Department of Bioengineering, Stanford University, Stanford, CA, USA.",
"Department of Bioengineering, Stanford University, Stanford, CA, USA.",
"Department of Genetics, Stanford University, Stanford, CA, USA.",
"Department of Biology, Stanford University, Stanford, CA, USA.",
"Department of Genetics, Stanford University, Stanford, CA, USA.",
"Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA, USA.",
"Biophysics Program, Stanford University, Stanford, CA, USA.",
"Department of Bioengineering, Stanford University, Stanford, CA, USA.",
"Department of Genetics, Stanford University, Stanford, CA, USA.",
"Department of Cancer Biology, Stanford University, Stanford, CA, USA.",
"Department of Cancer Biology, Stanford University, Stanford, CA, USA.",
"Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA, USA.",
"Department of Biomolecular Chemistry and Center for Human Genomics and Precision Medicine, University of Wisconsin-Madison, Madison, WI, USA.",
"Department of Genetics, Stanford University, Stanford, CA, USA.",
"Chan Zuckerberg Biohub-San Francisco, San Francisco, CA, USA.\nDepartment of Bioengineering, Stanford University, Stanford, CA, USA.\nSarafan ChEM-H, Stanford University, Stanford, CA, USA.",
"Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA, USA.\nWyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.",
"Department of Bioengineering, Stanford University, Stanford, CA, USA. [email protected].",
"Department of Genetics, Stanford University, Stanford, CA, USA. [email protected].\nSarafan ChEM-H, Stanford University, Stanford, CA, USA. [email protected]."
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39485013 | 301 | The future of cellular therapy for the treatment of renal cell carcinoma. | Systemic treatment options for renal cell carcinoma (RCC) have expanded considerably in recent years, and both tyrosine kinase inhibitors and immune checkpoint inhibitors, alone or in combination, have entered the clinical arena. Adoptive cell immunotherapies have recently revolutionized the treatment of cancer and hold the promise to further advance the treatment of RCC.
In this review, we summarize the latest preclinical and clinical development in the field of adoptive cell immunotherapy for the treatment of RCC, focusing on lymphokine-activated killer (LAK) cells, cytokine-induced killer (CIK) cells, tumor-infiltrating T cells (TILs), TCR-engineered T cells, chimeric antigen receptor (CAR) T cells, and dendritic cell vaccination strategies. Perspectives on emerging cellular products including CAR NK cells, CAR macrophages, as well as γδ T cells are also included.
So far, areas of greater therapeutic success of adoptive cell therapies include the adjuvant administration of CIK cells and the transfer of anti-CD70 CAR T cells in patients with metastatic RCC. Bench to bedside and back research will be needed to overcome current limitations of adoptive cell therapies in RCC, primarily aiming at improving the safety of immune cell products, optimizing their antitumor activity and generating off-the-shelf products ready for clinical use. | [
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] | 2024-11-01 | 1 | 39485013 | [
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"adoptive cell therapies",
"Adoptive cell immunotherapies",
"adoptive cell immunotherapy",
"immune cell products",
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"Adoptive cell therapy",
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] | 0 | 10.1080/14712598.2024.2418321 | [
"Chaoul",
"Lauricella",
"Giglio",
"D'Angelo",
"Ganini",
"Cives",
"Porta"
] | [
"Interdisciplinary Department of Medicine, University of Bari \"Aldo Moro\", Bari, Italy.",
"Interdisciplinary Department of Medicine, University of Bari \"Aldo Moro\", Bari, Italy.",
"Interdisciplinary Department of Medicine, University of Bari \"Aldo Moro\", Bari, Italy.",
"Interdisciplinary Department of Medicine, University of Bari \"Aldo Moro\", Bari, Italy.",
"Interdisciplinary Department of Medicine, University of Bari \"Aldo Moro\", Bari, Italy.\nDivision of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, Bari, Italy.",
"Interdisciplinary Department of Medicine, University of Bari \"Aldo Moro\", Bari, Italy.\nDivision of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, Bari, Italy.",
"Interdisciplinary Department of Medicine, University of Bari \"Aldo Moro\", Bari, Italy.\nDivision of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, Bari, Italy."
] | [
"39485013"
] | [] | 10.696733 | 4.31397 |
39479958 | 302 | Formin-like 1β phosphorylation at S1086 is necessary for secretory polarized traffic of exosomes at the immune synapse in Jurkat T lymphocytes. | We analyzed here how formin-like 1 β (FMNL1β), an actin cytoskeleton-regulatory protein, regulates microtubule-organizing center (MTOC) and multivesicular bodies (MVB) polarization and exosome secretion at an immune synapse (IS) model in a phosphorylation-dependent manner. IS formation was associated with transient recruitment of FMNL1β to the IS, which was independent of protein kinase C δ (PKCδ). Simultaneous RNA interference of all FMNL1 isoforms prevented MTOC/MVB polarization and exosome secretion, which were restored by FMNL1βWT expression. However, expression of the non-phosphorylatable mutant FMNL1βS1086A did not restore neither MTOC/MVB polarization nor exosome secretion to control levels, supporting the crucial role of S1086 phosphorylation in MTOC/MVB polarization and exosome secretion. In contrast, the phosphomimetic mutant, FMNL1βS1086D, restored MTOC/MVB polarization and exosome secretion. Conversely, FMNL1βS1086D mutant did not recover the deficient MTOC/MVB polarization occurring in PKCδ-interfered clones, indicating that S1086 FMNL1β phosphorylation alone is not sufficient for MTOC/MVB polarization and exosome secretion. FMNL1 interference inhibited the depletion of F-actin at the central region of the immune synapse (cIS), which is necessary for MTOC/MVB polarization. FMNL1βWT and FMNL1βS1086D, but not FMNL1βS1086A expression, restored F-actin depletion at the cIS. Thus, actin cytoskeleton reorganization at the IS underlies the effects of all these FMNL1β variants on polarized secretory traffic. FMNL1 was found in the IS made by primary T lymphocytes, both in T cell receptor (TCR) and chimeric antigen receptor (CAR)-evoked synapses. Taken together, these results point out a crucial role of S1086 phosphorylation in FMNL1β activation, leading to cortical actin reorganization and subsequent control of MTOC/MVB polarization and exosome secretion. | [
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] | 2024-10-31 | 90 | 39479958 | [
"MTOC",
"exosome secretion",
"MVB",
"cortical actin reorganization",
"actin cytoskeleton reorganization",
"S1086 phosphorylation",
"actin cytoskeleton",
"MTOC/MVB polarization",
"T cell receptor",
"protein kinase C δ",
"primary T lymphocytes",
"chimeric antigen receptor",
"FMNL1 interference",
"MVB) polarization",
"the deficient MTOC/MVB polarization",
"neither MTOC/MVB polarization",
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10.4049/jimmunol.1202496 | [
"Garcia-Rodriguez",
"Hidalgo",
"Rodriguez-Milla",
"Somovilla-Crespo",
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] | [
"Cellular Biotechnology Unit, Instituto de Salud Carlos III, Madrid, Spain.\nUniversidad Nacional de Educación a (UNED), Madrid, Spain.",
"Cellular Biotechnology Unit, Instituto de Salud Carlos III, Madrid, Spain.",
"Cellular Biotechnology Unit, Instituto de Salud Carlos III, Madrid, Spain.",
"Cellular Biotechnology Unit, Instituto de Salud Carlos III, Madrid, Spain.",
"Cellular Biotechnology Unit, Instituto de Salud Carlos III, Madrid, Spain.\nInstituto de Investigación de Enfermedades Raras (IIER) & Departamento de Desarrollo de Medicamentos de Terapias Avanzadas (DDMTA), Instituto de Salud Carlos III, Madrid, Spain."
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39475383 | 304 | Optimizing CAR-NK Cell Transduction and Expansion: Leveraging Cytokine Modulation for Enhanced Performance. | Cellular immunotherapy has emerged as one of the most potent approaches to treating cancer patients. Adoptive transfer of chimeric antigen receptor (CAR) T cells as well as the use of haploidentical natural killer (NK) cells can induce remission in patients with lymphoma and leukemia. Although the use of CAR T cells has been established, this approach is currently limited for wider use by the risk of severe adverse events, including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. Moreover, the risk of triggering graft vs host reactions in settings of allogeneic T cell infusion limits the use to autologous CAR T cells if advanced CRISPR engineering is not applied. In contrast, NK cell-based cancer immunotherapy has emerged as a safe approach even in allogeneic settings. However, efficient transduction of primary blood NK cells with vesicular stomatitis virus G glycoprotein (VSV-G) pseudotyped lentivirus commonly used for T cell modification remains challenging. This article presents a detailed method that significantly enhances the transduction efficiency of NK cells by utilizing a short-term culture in cytokine-supplemented medium. It also encompasses the preparation of high-titer and high-quality lentiviral particles for optimal NK cell transduction. Overall, this protocol details the step-by-step culture of NK cells in cytokine-supplemented medium, their transduction with VSV-G lentiviral vectors, and subsequent expansion for functional assays. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Isolation of NK cells from human peripheral blood mononuclear cells (PBMCs) Basic Protocol 2: NK cell expansion and transduction with lentivirus for generating CAR-NK cells Support Protocol 1: Plasmid amplification Support Protocol 2: Lentivirus preparation Support Protocol 3: Lentivirus titration. | [
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] | 2024-10-30 | 1 | 39475383 | [
"NK cells",
"NK cell expansion",
"optimal NK cell transduction",
"primary blood NK cells",
"CAR T cells",
"autologous CAR T cells",
"T cell modification",
"allogeneic T cell infusion",
"human peripheral blood mononuclear cells",
"NK cell-based cancer immunotherapy",
"CAR-NK cells",
"Lentivirus preparation Support Protocol",
"Plasmid amplification Support Protocol",
"efficient transduction",
"Support Protocol",
"Basic Protocol 2: NK cell expansion",
"transduction",
"cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome",
"wider use",
"CAR",
"Basic Protocol",
"cancer patients",
"subsequent expansion",
"chimeric antigen receptor",
"allogeneic settings",
"severe adverse events",
"haploidentical natural killer (NK) cells",
"Wiley Periodicals",
"vesicular stomatitis virus",
"advanced CRISPR engineering"
] | [
"CAR‐NK",
"IL‐12",
"cytokines",
"lentiviral production",
"lentiviral transduction"
] | 0 | 10.1002/cpz1.70040 | [
"Ingegnere",
"Segain",
"Cozzani",
"Carlsten",
"Mitra",
"Gaggero"
] | [
"Université de Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277 CANTHER, Lille, France.\nThese authors share first authorship.",
"Université de Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277 CANTHER, Lille, France.\nThese authors share first authorship.",
"Université de Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277 CANTHER, Lille, France.",
"Division of Biomolecular and Cellular Medicine, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.\nDepartment of Cell Therapy and Allogenic Stem Cell Transplantation, Karolinska Comprehensive Cancer Center, Karolinska University Hospital, Stockholm, Sweden.",
"Université de Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277 CANTHER, Lille, France.\nThese authors share final authorship.",
"Université de Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277 CANTHER, Lille, France.\nThese authors share final authorship."
] | [
"39475383"
] | [] | 11.396026 | 5.8061 |
39472748 | 305 | Specific ECM degradation potentiates the antitumor activity of CAR-T cells in solid tumors. | Although major progress has been made in the use of chimeric antigen receptor (CAR)-T-cell therapy for hematological malignancies, this method is ineffective against solid tumors largely because of the limited infiltration, activation and proliferation of CAR-T cells. To overcome this issue, we engineered CAR-T cells with synthetic Notch (synNotch) receptors, which induce local tumor-specific secretion of extracellular matrix (ECM)-degrading enzymes at the tumor site. SynNotch CAR-T cells achieve precise ECM recognition and robustly kill targeted tumors, with synNotch-induced enzyme production enabling the degradation of components of the tumor ECM. In addition, this regulation strongly increased the infiltration of CAR-T cells and the clearance of solid tumors, resulting in tumor regression without toxicity in vivo. Notably, synNotch CAR-T cells also promoted the persistent activation of CAR-T cells in patient-derived tumor organoids. Thus, we constructed a synthetic T-cell system that increases the infiltration and antitumor function of CAR-T cells, providing a strategy for targeting ECM-rich solid tumors. | [
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] | 2024-10-30 | 50 | 39472748 | [
"solid tumors",
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"CAR-T cells",
"chimeric antigen receptor",
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"the limited infiltration",
"vivo",
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] | [
"CAR-T cells",
"ECM-degrading enzymes",
"Infiltration",
"synNotch receptor"
] | 0 | 10.1038/s41423-024-01228-9 | [
"Zheng",
"Shen",
"Liang",
"Lyu",
"Zhang",
"Dong",
"Li",
"Han",
"Zhao",
"Zhang",
"Wang",
"Meng",
"Bai",
"Yang",
"Lu",
"Li",
"Yang",
"Zhang",
"Yan"
] | [
"State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, China.\nDepartment of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China.",
"Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.\nAir Force Hospital of Western Theater Command, Chengdu, Sichuan, 610065, China.",
"State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, China.\nDepartment of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China.",
"Department of Obstetrics and Gynecology, Xijing Hospital of Fourth Military Medical University, Xi'an, Shaanxi, China.",
"Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.\nDepartment of Ultrasound, The first affliated hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, Shaanxi, China.",
"State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, China.\nSchool of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, China.",
"Department of Obstetrics and Gynecology, Xijing Hospital of Fourth Military Medical University, Xi'an, Shaanxi, China.",
"State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, China.\nSchool of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, China.",
"State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, China.",
"State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, China.",
"State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, China.\nDepartment of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China.",
"State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, China.\nCollege of Life Science, Yan'an University, Yan'an, Shaanxi, China.",
"State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, China.",
"State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, China.\nCollege of Life Science, Yan'an University, Yan'an, Shaanxi, China.",
"State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi' an, Shaanxi, China.",
"Department of Obstetrics and Gynecology, Xijing Hospital of Fourth Military Medical University, Xi'an, Shaanxi, China. [email protected].",
"Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China. [email protected].",
"Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China. [email protected].",
"State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, China. [email protected]."
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39471818 | 306 | Integrative single-cell multi-omics of CD19-CAR | The impact of phenotypic, clonal, and functional heterogeneity of chimeric antigen receptor (CAR)-T cells on clinical outcome remains understudied. Here, we integrate clonal kinetics with transcriptomic heterogeneity resolved by single-cell omics to interrogate cellular dynamics of non-transduced (CAR | [
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10.1038/s41586-020-2056-8 | [
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"Josep Carreras Leukemia Research Institute, Barcelona, Spain; PhD programme in Biomedicine, University of Barcelona, Barcelona, Spain.",
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"Cancer Research Centre (IBMCC, USAL-CSIC), Institute for Biomedical Research of Salamanca (IBSAL) and Department of Medicine and Cytometry Service (NUCLEUS Research Support Platform), University of Salamanca (USAL), Salamanca, Spain.",
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"Pediatric Oncology and Hematology Department, Hospital Sant Joan de Déu de Barcelona, Barcelona, Spain; Institut de Recerca Sant Joan de Déu, Barcelona, Spain.",
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"Josep Carreras Leukemia Research Institute, Barcelona, Spain; Spanish Network for Advanced Therapies, RICORS-TERAV, ISCIII, Spain; Department of Hematology, Hospital Clinic de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.",
"Spanish Network for Advanced Therapies, RICORS-TERAV, ISCIII, Spain; Department of Hematology, Hospital Clinic de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Spanish Collaborative Cancer Network, CIBERONC, ISCIII, Spain.",
"Cancer Research Centre (IBMCC, USAL-CSIC), Institute for Biomedical Research of Salamanca (IBSAL) and Department of Medicine and Cytometry Service (NUCLEUS Research Support Platform), University of Salamanca (USAL), Salamanca, Spain; Spanish Collaborative Cancer Network, CIBERONC, ISCIII, Spain.",
"Josep Carreras Leukemia Research Institute, Barcelona, Spain. Electronic address: [email protected].",
"Josep Carreras Leukemia Research Institute, Barcelona, Spain; Spanish Network for Advanced Therapies, RICORS-TERAV, ISCIII, Spain; Spanish Collaborative Cancer Network, CIBERONC, ISCIII, Spain. Electronic address: [email protected].",
"Josep Carreras Leukemia Research Institute, Barcelona, Spain; Spanish Network for Advanced Therapies, RICORS-TERAV, ISCIII, Spain; Spanish Collaborative Cancer Network, CIBERONC, ISCIII, Spain; Department of Biomedicine, University of Barcelona, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. Electronic address: [email protected]."
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39471490 | 307 | Cancer cachexia and weight loss before CAR T-cell therapy for lymphoma are independently associated with poor outcomes. | Chimeric antigen receptor (CAR) T-cell therapy has transformed the care of lymphoma, yet many patients relapse. Several prognostic markers have been associated with CAR T-cell outcomes, such as tumor burden, response to bridging chemotherapy, and laboratory parameters at the time of lymphodepletion or infusion. The effect of cancer cachexia and weight loss before CAR T cells on toxicity and outcomes is not well understood. Here, we present a retrospective single-institution cohort study of 259 patients with lymphoma treated with CAR T cells between 2017 and 2023. We observed that patients with >5% decrease in their body mass index in the 3 months preceding CAR T-cell treatment (weight loss group; all meeting one of the commonly accepted definitions of cancer cachexia) had higher disease burden and inflammatory parameters (C-reactive protein, ferritin, interleukin-6, and tumor necrosis factor α) at the time of lymphodepletion and CAR T-cell infusion. Patients with weight loss experienced higher rates of grade 3+ neurotoxicity and early hematotoxicity, but those effects were not seen upon multivariable adjustment. However, in both univariate and multivariable analysis, patients with weight loss had worse response rates, overall survival, and event-free survival, indicating that weight loss is an independent poor prognostic factor. Our data suggest that weight loss in the 3 months preceding CAR T-cell therapy represents a worrisome "alarm signal" and a potentially modifiable factor, alongside tumor burden and inflammation, and warrants further investigation in patients treated with CAR T-cell therapy. | [
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] | 2024-10-30 | 1 | 39471490 | [
"CAR T cells",
"weight loss",
"weight loss group",
"tumor burden",
"many patients",
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"CAR T-cell outcomes",
"tumor necrosis factor",
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"patients",
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"CAR T-cell treatment",
"higher disease burden",
"worse response rates",
"higher rates",
"cancer cachexia",
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"laboratory parameters",
"CAR) T-cell therapy",
"that weight loss",
"overall survival",
"Several prognostic markers",
"early hematotoxicity",
"multivariable adjustment",
"response",
"further investigation",
"lymphoma",
"Chimeric antigen receptor",
"lymphodepletion",
"outcomes"
] | [] | 0 | 10.1182/bloodadvances.2024014555 | [
"Valtis",
"Devlin",
"Shouval",
"Rejeski",
"Corona",
"Luna De Abia",
"Rivas-Delgado",
"Luttwak",
"Cassanello",
"Landego",
"Schöder",
"Bedmutha",
"Boardman",
"Shah",
"Scordo",
"Perales",
"Salles",
"Palomba",
"Shah",
"Park"
] | [
"Cell Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.",
"Biostatistics Service, Memorial Sloan Kettering Cancer Center, New York, NY.",
"Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.",
"Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.\nDepartment of Medicine III-Hematology/Oncology, LMU University Hospital, Ludwig Maximilian University of Munich, Munich, Germany.",
"Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.",
"Adult Bone Marrow Transplantation Unit, Hematology Service, Hospital Universitario Ramón y Cajal, Madrid, Spain.",
"Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.",
"Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.",
"Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.\nDepartment of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.",
"Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.\nDepartment of Internal Medicine, Max Rady Faculty of Health Sciences, Section of Medical Oncology and Hematology, University of Manitoba, Manitoba, Canada.",
"Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY.",
"Department of Nuclear Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.",
"Cell Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.\nLymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.",
"Adult Bone Marrow Transplantation Unit, Hematology Service, Hospital Universitario Ramón y Cajal, Madrid, Spain.",
"Adult Bone Marrow Transplantation Unit, Hematology Service, Hospital Universitario Ramón y Cajal, Madrid, Spain.",
"Adult Bone Marrow Transplantation Unit, Hematology Service, Hospital Universitario Ramón y Cajal, Madrid, Spain.\nDepartment of Medicine, Weill Cornell Medical College, New York, NY.",
"Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.",
"Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.",
"Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.",
"Cell Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY."
] | [
"39471490"
] | [] | 6.120437 | 4.946892 |
39469946 | 308 | Emerging CART Therapies for Pediatric Acute Myeloid Leukemia. | The prognosis of children with acute myeloid leukemia (AML) has improved incrementally over the last decades. However, at relapse, overall survival (OS) ∼40% to 50% and is even lower for patients with chemorefractory disease. Effective and less-toxic therapies are urgently needed for these children. In the last years, immune-directed therapies such as chimeric antigen receptor (CAR)-T cells were introduced, which showed outstanding clinical activity against B-cell malignancies. CART therapies are being developed for AML on the basis of the results obtained for other hematologic malignancies. The biggest challenge of CART therapy for AML is to identify a specific target antigen, since antigens expressed in AML cells are usually shared with healthy hematopoietic stem cells. An overview of prospects of CART in pediatric AML, focused on the common antigens targeted by CART in AML that have been tested or are currently under investigation, is provided in this manuscript. | [
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] | 2024-10-29 | 1 | 39469946 | [
"AML cells",
"pediatric AML",
"AML",
"CART therapies",
"CART therapy",
"chimeric antigen receptor",
"healthy hematopoietic stem cells",
"CAR)-T cells",
"antigens",
"acute myeloid leukemia",
"outstanding clinical activity",
"other hematologic malignancies",
"CART",
"chemorefractory disease",
"OS",
"immune-directed therapies",
"children",
"a specific target antigen",
"B-cell malignancies",
"patients",
"myeloid",
"(AML",
"the common antigens",
"investigation",
"relapse, overall survival",
"prospects",
"the last years",
"the last decades",
"Effective and less-toxic therapies",
"The biggest challenge"
] | [] | 0 | 10.1097/MPH.0000000000002956 | [
"Ceolin",
"Spadea",
"Apolito",
"Saglio",
"Fagioli"
] | [
"Department of Pediatric Oncology/Hematology, Regina Margherita Children's Hospital.",
"Department of Pediatric Oncology/Hematology, Regina Margherita Children's Hospital.\nDepartment of Pediatric Oncology/Hematology, University of Turin, Turin, Italy.",
"Department of Pediatric Oncology/Hematology, Regina Margherita Children's Hospital.",
"Department of Pediatric Oncology/Hematology, Regina Margherita Children's Hospital.",
"Department of Pediatric Oncology/Hematology, Regina Margherita Children's Hospital.\nDepartment of Pediatric Oncology/Hematology, University of Turin, Turin, Italy."
] | [
"39469946"
] | [] | 6.809262 | 7.186608 |
39469704 | 309 | Naturally selected CD7-directed CAR-T bridging allo-HSCT in refractory acute myeloid leukemia: a case report and review. | Relapsed/refractory acute myeloid leukemia (R/R-AML) has a poor prognosis. CD7 is expressed in leukemic cells in 30% of patients with AML but not in normal myeloid cells. Therefore, it can be a potential target for immunotherapy in patients with R/R-AML. Naturally selected CD7-directed chimeric antigen receptor T cells (CAR-T) have promising effects against AML based on xenotransplantation models. We report a R/R-AML case that achieved complete remission with incomplete hematologic recovery with naturally selected CD7 CAR-T therapy. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) as consolidation early after CAR T therapy, the patient experienced 12 months of disease-free survival to date. Our results confirmed that allogeneic hematopoietic stem cell transplantation after naturally selected CD7 CAR-T therapy can be a potential treatment for patients with CD7-positive R/R-AML. | [
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"a potential target",
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"12 months"
] | [
"CRS",
"HSCT",
"acute myeloid leukemia",
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] | 0 | 10.3389/fimmu.2024.1461908
10.1002/ajh.25162
10.1182/blood-2011-11-325050
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10.1186/s40164-022-00318-6
10.3390/ijms21113886 | [
"Liu",
"Xu",
"Li",
"Zhang",
"Li",
"Li",
"Wang"
] | [
"Department of Hematology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Hematology, Shijiazhuang, Hebei, China.",
"Department of Hematology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Hematology, Shijiazhuang, Hebei, China.",
"Department of Hematology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Hematology, Shijiazhuang, Hebei, China.",
"Department of Hematology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Hematology, Shijiazhuang, Hebei, China.",
"Hebei Senlang Biotechnology Co, Shijiazhuang, China.",
"Department of Histology and Embryology, Hebei Medical University, Shijiazhuang, Hebei, China.",
"Department of Hematology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Hematology, Shijiazhuang, Hebei, China."
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] | [] | 6.531301 | 5.997415 |
39468753 | 310 | Therapeutic targeting of the protein tyrosine kinase-7 in cancer: an overview. | The protein tyrosine kinase-7 (PTK7) is an evolutionarily conserved transmembrane receptor that has emerged as a potential therapeutic target for human tumors. PTK7 is a pseudokinase that is involved in the modulation of the Wnt signaling pathway through interactions with other receptors. These interactions result in targeted gene activation that regulates cell polarity, migration, and proliferation during embryogenesis. Aside of this role during development, PTK7 has been shown as overexpressed in numerous cancers including colon carcinoma, leukemia, neuroblastoma, hepatoma, and ovarian cancer. The activity of PTK7 and the direct correlation with poor prognosis have fostered preclinical investigations and phase I clinical trials, aiming at inhibiting PTK7 and inducing antitumoral effects. In this review, we provide an exhaustive overview of the diverse approaches that use PTK7 as a new molecular target for cancer therapy in different tumor types. We discuss current therapies and future strategies including chimeric antigen receptor-T cells, antibody-drug conjugates, aptamers, based on up-to-date literature and ongoing research progress. | [
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] | 2024-10-29 | 1 | 39468753 | [
"PTK7",
"cancer therapy",
"numerous cancers",
"cell polarity",
"other receptors",
"ovarian cancer",
"targeted gene activation",
"current therapies",
"different tumor types",
"ongoing research progress",
"poor prognosis",
"preclinical investigations",
"signaling pathway",
"chimeric antigen receptor-T cells",
"future strategies",
"colon carcinoma",
"human tumors",
"interactions",
"antitumoral effects",
"date",
"aptamers",
"Wnt",
"phase",
"leukemia",
"(PTK7",
"migration",
"a potential therapeutic target",
"a new molecular target",
"hepatoma",
"antibody-drug conjugates"
] | [
"CAR-T cell",
"PTK7",
"antibody-drug conjugate",
"aptamer",
"cancer therapy",
"targeted therapy"
] | 0 | 10.1093/oncolo/oyae290 | [
"Mottard",
"Cokaiko",
"Rogister",
"Neirinckx"
] | [
"Laboratory of Nervous System Diseases and Therapy, GIGA Institute, University of Liège, 4000 Liège, Belgium.",
"Laboratory of Nervous System Diseases and Therapy, GIGA Institute, University of Liège, 4000 Liège, Belgium.",
"Laboratory of Nervous System Diseases and Therapy, GIGA Institute, University of Liège, 4000 Liège, Belgium.\nNeurology Department, University Hospital, University of Liège, 4000 Liège, Belgium.",
"Laboratory of Nervous System Diseases and Therapy, GIGA Institute, University of Liège, 4000 Liège, Belgium."
] | [
"39468753"
] | [] | 10.12507 | 6.413344 |
39468646 | 311 | Trogocytosis in CAR immune cell therapy: a key mechanism of tumor immune escape. | Immune cell therapy based on chimeric antigen receptor (CAR) technology platform has been greatly developed. The types of CAR immune cell therapy have expanded from T cells to innate immune cells such as NK cells and macrophages, and the diseases treated have expanded from hematological malignancies to non-tumor fields such as infectious diseases and autoimmune diseases. Among them, CAR-T and CAR-NK therapy have observed examples of rapid remission in approved clinical trials, but the efficacy is unstable and plagued by tumor resistance. Trogocytosis is a special phenomenon of intercellular molecular transfer that is common in the immune system and is achieved by recipient cells through acquisition and internalization of donor cell-derived molecules and mediates immune effects. Recently, a novel short-term drug resistance mechanism based on trogocytosis has been proposed, and the bidirectional molecular exchange between CAR immune cells and tumor cells triggered by trogocytosis partially explains the long-term relapse phenomenon after treatment with CAR immune cells. In this review, we summarize the research progress of trogocytosis in CAR immunotherapy, discuss the influencing factors of trogocytosis and its direct and indirect interference with CAR immune cells and emphasize that the interference of trogocytosis can further release the potential of CAR immune cell therapy. | [
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] | 2024-10-29 | 88 | 39468646 | [
"CAR immune cells",
"CAR immune cell therapy",
"Immune cell therapy",
"immune cells",
"NK cells",
"tumor cells",
"recipient cells",
"T cells",
"Trogocytosis",
"trogocytosis",
"CAR immunotherapy",
"CAR",
"intercellular molecular transfer",
"non-tumor fields",
"infectious diseases",
"tumor resistance",
"approved clinical trials",
"donor cell-derived molecules and mediates immune effects",
"autoimmune diseases",
"rapid remission",
"hematological malignancies",
"CAR-NK therapy",
"the immune system",
"chimeric antigen receptor (CAR) technology platform",
"CAR-T",
"examples",
"a novel short-term drug resistance mechanism",
"macrophages",
"the bidirectional molecular exchange",
"treatment"
] | [
"CAR-NK",
"CAR-T",
"Fratricide",
"Immune escape",
"Trogocytosis"
] | 0 | 10.1186/s12964-024-01894-2 | [
"Chen",
"Xin",
"Zhu",
"Qiu",
"Qiu",
"Li",
"Tu"
] | [
"Department of Pharmacy, Hefei First People's Hospital, The Third Affiliated Hospital of Anhui Medical University, 390# Huaihe Road, Luyang District, Hefei, China.",
"Anhui Women and Children's Medical Center, Hefei Maternal and Child Health Hospital, Hefei, China.",
"Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, 81# Meishan Road, Shushan District, Hefei, China.",
"Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, 81# Meishan Road, Shushan District, Hefei, China.",
"Department of Pharmacy, Hefei First People's Hospital, The Third Affiliated Hospital of Anhui Medical University, 390# Huaihe Road, Luyang District, Hefei, China. [email protected].",
"Department of Pharmacy, Hefei First People's Hospital, The Third Affiliated Hospital of Anhui Medical University, 390# Huaihe Road, Luyang District, Hefei, China. [email protected].",
"Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, 81# Meishan Road, Shushan District, Hefei, China. [email protected]."
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] | [] | 8.973466 | 4.419855 |
39468591 | 312 | Development and validation of the post-CAR prognostic index for large B-cell lymphoma patients after CAR-T progression in third or later line treatment. | Chimeric antigen receptor (CAR) T-cell therapy fails to achieve durable responses in over 60% of relapsed/refractory (R/R) large B-cell lymphoma (LBCL) patients in the third or later line setting. After CAR-T failure, survival outcomes are heterogeneous and a prognostic model in this patient population is lacking. A training cohort of 216 patients with progressive disease (PD) after CAR-T from 12 Spanish centers was used to develop the Post-CAR Prognostic Index (PC-PI); primary endpoint was overall survival (OS) from CAR-T progression. Validation was performed in an external cohort from three different European centers (n = 204). The prognostic score incorporated five variables, assessed at time of PD to CAR-T: ECOG (> 0), hemoglobin (< 10 g/dL), LDH (≥ 2xULN), number of extranodal sites (> 1) and time from CAR-T to PD (< 4 months). Patients were classified in four risk groups with distinct OS (p-value < 0.05 in all comparisons). In the validation cohort, median OS in the low (31%), intermediate-low (26%), intermediate-high (17%) and high risk (26%) were 15.7, 7.1, 1.8 and 1.0 months, respectively (p < 0.05 in all comparisons). Results were consistent following adjustment for subsequent treatment. In the external cohort, the PC-PI showed a C-statistic of 0.79 (95%CI 0.76-0.82), outperforming IPI and R-IPI. In conclusion, the PC-PI score is a novel tool for OS prediction and could facilitate risk-adapted management of LBCL patients relapsing after CAR T-cells. Additionally, these results will help stratification and interpretation of trials and real-world data incorporating CART-exposed patients. | [
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] | 2024-10-29 | 37 | 39468591 | [
"LBCL patients",
"Patients",
"distinct OS",
"OS prediction",
"high risk",
"median OS",
"CAR T-cells",
"PI",
"survival outcomes",
"overall survival",
"the Post-CAR Prognostic Index",
"CAR-T",
"CAR-T progression",
"time",
"extranodal sites",
"LBCL",
"primary endpoint",
"subsequent treatment",
"progressive disease",
"durable responses",
"Chimeric antigen receptor",
"CAR) T-cell therapy",
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"adjustment",
"interpretation",
"trials",
"IPI",
"stratification",
"third"
] | [
"CAR-T",
"Disease progression",
"Large B-cell lymphoma",
"Overall survival",
"Score"
] | 0 | 10.1186/s13045-024-01608-8 | [
"Iacoboni",
"Navarro",
"Sesques",
"Rejeski",
"Bastos-Oreiro",
"Serpenti",
"Martin Lopez",
"Iraola-Truchuelo",
"Delgado",
"Perez",
"Guerreiro",
"Caballero",
"Martinez-Cibrian",
"Luzardo Henriquez",
"Sanchez Pina",
"Sancho",
"Ghesquieres",
"Mussetti",
"Lopez Corral",
"Hernani",
"Reguera",
"Sureda",
"Bosch",
"Martin Garcia-Sancho",
"Kwon",
"Subklewe",
"Kuhnl",
"Bachy",
"Barba",
"Villacampa",
"Abrisqueta"
] | [
"Department of Hematology, University Hospital Vall d'Hebron, Barcelona, Spain. [email protected].\nExperimental Hematology, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. [email protected].",
"Statistics Unit, Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain.",
"Centre Hospitalier Lyon Sud, Lyon, France.",
"Department of Medicine III - Hematology/Oncology, LMU University Hospital, LMU Munich, Munich, Germany.\nAdult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA.",
"Department of Hematology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.",
"Department of Hematology, King's College Hospital, London, UK.",
"Hematology Department, IBSAL, CIBERONC, University Hospital of Salamanca, University of Salamanca, Salamanca, Spain.",
"Experimental Hematology, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.",
"Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS), CSIC, Universidad de Sevilla, Seville, Spain.",
"Hematology Department, Hospital Clínico Universitario, INCLIVA Research Institute, Valencia, Spain.",
"Hematology Department, Hospital Universitario La Fe, Instituto de Investigación Sanitaria La Fe (IIS-La Fe), Valencia, Spain.",
"Department of Hematology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.",
"Hematology Department, Hospital Clínic, Barcelona, Spain.",
"Department of Hematology, Hospital Universitario de Gran Canaria Doctor Negrín, Islas Canarias, Spain.",
"Department of Hematology, Hospital Universitario 12 de Octubre, Madrid, Spain.",
"Hematology Department, ICO-IJC Hospital Germans Trias i Pujol, Barcelona, Spain.",
"Centre Hospitalier Lyon Sud, Lyon, France.",
"Clinical Hematology Department, Institut Català d'Oncologia - L'Hospitalet de Llobregat, IDIBELL, Universitat de Barcelona, Barcelona, Spain.",
"Hematology Department, IBSAL, CIBERONC, University Hospital of Salamanca, University of Salamanca, Salamanca, Spain.",
"Hematology Department, Hospital Clínico Universitario, INCLIVA Research Institute, Valencia, Spain.",
"Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS), CSIC, Universidad de Sevilla, Seville, Spain.",
"Clinical Hematology Department, Institut Català d'Oncologia - L'Hospitalet de Llobregat, IDIBELL, Universitat de Barcelona, Barcelona, Spain.",
"Department of Hematology, University Hospital Vall d'Hebron, Barcelona, Spain.\nExperimental Hematology, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.",
"Hematology Department, IBSAL, CIBERONC, University Hospital of Salamanca, University of Salamanca, Salamanca, Spain.",
"Department of Hematology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.",
"Department of Medicine III - Hematology/Oncology, LMU University Hospital, LMU Munich, Munich, Germany.",
"Department of Hematology, King's College Hospital, London, UK.",
"Centre Hospitalier Lyon Sud, Lyon, France.",
"Department of Hematology, University Hospital Vall d'Hebron, Barcelona, Spain.\nExperimental Hematology, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.",
"Statistics Unit, Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain.",
"Department of Hematology, University Hospital Vall d'Hebron, Barcelona, Spain.\nExperimental Hematology, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain."
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] | [] | 6.180521 | 5.334891 |
39466477 | 313 | CAR T-cell Therapy for Central Nervous System Lymphoma. | While anti-CD19 CAR T-cell therapy represents a major advance in systemic diffuse large B-cell lymphomas, central nervous system (CNS) lymphomas have been excluded from pivotal trials because of the fear of neurotoxicity. The purpose of this review was to assess the efficacy and tolerance of CAR T-cells in CNS lymphomas based on recently published studies.
All the studies on CAR T-cell therapy for both primary and secondary CNS lymphomas reported high response rates (complete response rates ranging from 32 to 67%) in highly pre-treated patients. One-year PFS reached 40 to 60% in several studies. Neurotoxicity occurred in 36 to 68% of patients, including grade 3-4 neurotoxicity in 4.5 to 29% of patients. CAR T-cell therapy appears to be a very promising treatment in CNS lymphomas, with efficacy results close to those observed in systemic lymphomas. The toxicity profile, notably regarding neurotoxicity, is reassuring and should not prevent the development of CAR T-cells in the disease. | [
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10.1182/bloodadvances.2020002328 | [
"Houillier",
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] | [
"Neurooncology Department, Groupe Hospitalier Pitié-Salpêtrière, APHP, Sorbonne Université, Inserm, CNRS, UMR S 1127, ICM, IHU, Paris, France. [email protected].",
"Clinical Hematology Department, Groupe Hospitalier Pitié-Salpêtrière, APHP-Sorbonne Université, Paris, France."
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39466110 | 314 | Optimising CAR T therapy for the treatment of solid tumors. | Adoptive immunotherapy using chimeric antigen receptor (CAR)-engineered T cells has proven transformative in the management of B cell and plasma cel derived malignancies. However, solid tumors have largely proven to be resistant to this therapeutic modality. Challenges include the paucity of safe target antigens, heterogeneity of target expression within the tumor, difficulty in delivery of CAR T cells to the site of disease, poor penetration within solid tumor deposits and inability to circumvent the array of immunosuppressive and biophysical barriers imposed by the solid tumor microenvironment.
Literature was reviewed on the PubMed database, excluding occasional papers which were not available as open access publications or through other means.
Here, we have surveyed the large body of technological advances that have been made in the quest to bridge the gap toward successful deployment of CAR T cells for the treatment of solid tumors. These encompass the development of more sophisticated targeting strategies to engage solid tumor cells safely and comprehensively, improved drug delivery solutions, design of novel CAR architectures that achieve improved functional persistence and which resist physical, chemical and biological hurdles present in tumor deposits. Prospects for combination therapies that incorporate CAR T cells are also considered. | [
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] | 2024-10-28 | 1 | 39466110 | [
"solid tumor cells",
"CAR T cells",
"solid tumors",
"solid tumor deposits",
"CAR)-engineered T cells",
"tumor deposits",
"B cell",
"safe target antigens",
"novel CAR architectures",
"chimeric antigen receptor",
"open access publications",
"improved functional persistence",
"CAR",
"occasional papers",
"target expression",
"technological advances",
"the solid tumor microenvironment",
"successful deployment",
"poor penetration",
"combination therapies",
"delivery",
"other means",
"Adoptive immunotherapy",
", improved drug delivery solutions",
"derived malignancies",
"PubMed",
"plasma",
"inability",
"the tumor",
"design"
] | [
"CAR T cell",
"CAR T cell delivery",
"CAR architecture",
"Cancer",
"Chimeric antigen receptor",
"combination therapies",
"solid tumors",
"tumor microenvironment"
] | 0 | 10.1080/14737140.2024.2421194 | [
"Mobark",
"Hull",
"Maher"
] | [
"King's College London, School of Cancer and Pharmaceutical Sciences, Guy's Hospital, London, UK.\nDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt.",
"Leucid Bio Ltd., Guy's Hospital, London, UK.",
"King's College London, School of Cancer and Pharmaceutical Sciences, Guy's Hospital, London, UK.\nLeucid Bio Ltd., Guy's Hospital, London, UK.\nDepartment of Immunology, Eastbourne Hospital, Eastbourne, East Sussex, UK."
] | [
"39466110"
] | [] | 9.627637 | 4.784219 |
39466024 | 315 | Phase 1 Study of ROR1 Specific CAR T Cells in Advanced Hematopoietic and Epithelial Malignancies. | The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is expressed in hematopoietic and epithelial cancers but has limited expression on normal adult tissues. This phase 1 study evaluated the safety of targeting ROR1 with autologous T-lymphocytes engineered to express a ROR1 chimeric antigen receptor (CAR). Secondary objectives evaluated persistence, trafficking, and antitumor activity of CAR T cells.
Twenty-one patients with ROR1+ tumors received CAR T cells at one of four dose levels (DL): 3.3x105/1x106/3.3x106/1x107 cells/kg, administered after lymphodepletion with Cyclophosphamide/Fludarabine (Cy/Flu) or Oxaliplatin/Cyclophosphamide (Ox/Cy). Cohort A included patients with chronic lymphocytic leukemia (CLL, n=3); cohort B included patients with triple-negative breast cancer (TNBC, n=10) or non-small-cell lung cancer (NSCLC, n=8). A second infusion was administered to one patient in cohort A with residual CLL in the marrow and three patients in cohort B with stable disease after first infusion.
Treatment was well tolerated apart from one dose limiting toxicity at DL4 in a patient with advanced NSCLC. Two of the three (67%) CLL patients showed robust CAR T expansion and a rapid antitumor response. In patients with NSCLC and TNBC, CAR T cells expanded to variable levels, infiltrated tumor poorly, and one of eighteen patients (5.5%) achieved partial response by RECIST 1.1.
ROR1 CAR T cells were well tolerated in most patients. Antitumor activity was observed in CLL but was limited in TNBC and NSCLC. Immunogenicity of the CAR and lack of sustained tumor infiltration were identified as limitations. | [
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] | [] | 0 | 10.1158/1078-0432.CCR-24-2172 | [
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"Fred Hutchinson Cancer Center, Seattle, Washington, United States.",
"University of Washington, Seattle, Washington, United States.",
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"Fred Hutchinson Cancer Center, Seattle, Washington, United States.",
"Fred Hutchinson Cancer Center, Seattle, WA, United States.",
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"Fred Hutchinson Cancer Center, Seattle, Washington, United States.",
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"Fred Hutchinson Cancer Center, Seattle, WA, United States.",
"Brown University, Port Townsend, WA, United States.",
"Fred Hutchinson Cancer Center, Seattle, Washington, United States.",
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] | [
"39466024"
] | [] | 6.521384 | 5.703856 |
39464890 | 316 | Bidirectional regulation of the cGAS-STING pathway in the immunosuppressive tumor microenvironment and its association with immunotherapy. | Adaptive anti-tumor immunity is currently dependent on the natural immune system of the body. The emergence of tumor immunotherapy has improved prognosis and prolonged the survival cycle of patients. Current mainstream immunotherapies, including immune checkpoint blockade, chimeric antigen receptor T-cell immunotherapy, and monoclonal antibody therapy, are linked to natural immunity. The cGAS-STING pathway is an important natural immunity signaling pathway that plays an important role in fighting against the invasion of foreign pathogens and maintaining the homeostasis of the organism. Increasing evidence suggests that the cGAS-STING pathway plays a key role in tumor immunity, and the combination of STING-related agonists can significantly enhance the efficacy of immunotherapy and reduce the emergence of immunotherapeutic resistance. However, the cGAS-STING pathway is a double-edged sword, and its activation can enhance anti-tumor immunity and immunosuppression. Immunosuppressive cells, including M2 macrophages, MDSC, and regulatory T cells, in the tumor microenvironment play a crucial role in tumor escape, thereby affecting the immunotherapy effect. The cGAS-STING signaling pathway can bi-directionally regulate this group of immunosuppressive cells, and targeting this pathway can affect the function of immunosuppressive cells, providing new ideas for immunotherapy. In this study, we summarize the activation pathway of the cGAS-STING pathway and its immunological function and elaborate on the key role of this pathway in immune escape mediated by the tumor immunosuppressive microenvironment. Finally, we summarize the mainstream immunotherapeutic approaches related to this pathway and explore ways to improve them, thereby providing guidelines for further clinical services. | [
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10.1021/acs.jmedchem.3c00907 | [
"Zhang",
"Wang",
"Mu",
"Zhu",
"Dong"
] | [
"Department of Immunology, Binzhou Medical University, Yantai, China.",
"Department of Immunology, Binzhou Medical University, Yantai, China.",
"School of Computer and Control Engineering, Yantai University, Yantai, China.",
"School of Computer and Control Engineering, Yantai University, Yantai, China.",
"Department of Immunology, Binzhou Medical University, Yantai, China."
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39464114 | 317 | Efficient multiplex non-viral engineering and expansion of polyclonal γδ CAR-T cells for immunotherapy. | Gamma delta (γδ) T cells are defined by their unique ability to recognize a limited repertoire of non-peptide, non-MHC-associated antigens on transformed and pathogen-infected cells. In addition to their lack of alloreactivity, γδ T cells exhibit properties distinct from other lymphocyte subsets, prompting significant interest in their development as an off-the-shelf cellular immunotherapeutic. However, their low abundance in circulation, heterogeneity, limited methods for | [
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"γδ T cells",
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"the-shelf"
] | [] | 0 | 10.1101/2024.09.03.611042
10.1016/j.medj.2022.07.008
10.1016/j.ymthe.2024.04.024
10.1101/2024.02.26.582108
10.1038/s41551-023-01157-4 | [
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"Johnson",
"Kim",
"Wenthe",
"Krueger",
"Wick",
"Kluesner",
"Crane",
"Bell",
"Skeate",
"Moriarity",
"Webber"
] | [
"Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.\nMasonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.\nCenter for Genome Engineering, University of Minnesota, Minneapolis, MN, USA.\nDepartment of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA.",
"Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.\nMasonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.\nCenter for Genome Engineering, University of Minnesota, Minneapolis, MN, USA.",
"Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.\nMasonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.\nCenter for Genome Engineering, University of Minnesota, Minneapolis, MN, USA.",
"Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.\nMasonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.\nCenter for Genome Engineering, University of Minnesota, Minneapolis, MN, USA.",
"Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.\nMasonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.\nCenter for Genome Engineering, University of Minnesota, Minneapolis, MN, USA.",
"Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.\nMasonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.\nCenter for Genome Engineering, University of Minnesota, Minneapolis, MN, USA.",
"Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, USA.\nHuman Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.",
"Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.\nMasonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.\nCenter for Genome Engineering, University of Minnesota, Minneapolis, MN, USA.",
"Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.\nMasonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.\nCenter for Genome Engineering, University of Minnesota, Minneapolis, MN, USA.",
"Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.\nMasonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.\nCenter for Genome Engineering, University of Minnesota, Minneapolis, MN, USA.",
"Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.\nMasonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.\nCenter for Genome Engineering, University of Minnesota, Minneapolis, MN, USA.\nStem Cell Institute, University of Minnesota, Minneapolis, MN, USA.",
"Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.\nMasonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.\nCenter for Genome Engineering, University of Minnesota, Minneapolis, MN, USA.\nStem Cell Institute, University of Minnesota, Minneapolis, MN, USA."
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] | [] | 10.214959 | 4.355821 |
39462383 | 318 | Targeting CD5 chimeric antigen receptor-engineered natural killer cells against T-cell malignancies. | Chimeric antigen receptor engineered T cells (CAR-T) have demonstrated promising clinical efficacy in B-cell malignancies, and the approach has been extended to T-cell malignancies. However, the use of allogeneic T cells in CAR therapy poses a challenge due to the risk of graft-versus-host disease. Recently, natural killer (NK) cells have exhibited "off‑the‑shelf" availability. The nanobody-based CAR structures have attracted much attention for their therapeutic potential owing to the advantages of nanobody, including small size, optimal stability, high affinity and manufacturing feasibility. CD5, a common surface marker of malignant T cells, has three scavenger receptor cysteine-rich domains (D1-D3) in the extracellular region. The present study aims to construct "off‑the‑shelf" CAR-NK cells targeting the membrane-proximal domain of CD5 derived from nanobody against T-cell malignancies.
Anti-CD5-D3 nanobody was screened by phage display technology, followed by constructing fourth-generation CAR plasmids ectopically producing IL-15 to generate CD5 CAR-NK cells derived from peripheral blood. And the second-generation CD5 CAR-T cells based on nanobody were generated, referred to as 5D.b CAR-T and 12 C.b CAR-T. Furthermore, CAR-NK cells without IL-15 (IL-15
Two nanobodies (5D and 12 C) competed for binding to the epitope of CD5-D3. 12 C CAR-NK cells were superior to 5D CAR-NK cells in antitumor potential and 12 C.b CAR-T cells exhibited superior cytotoxic activity than 5D CAR-T cells ex vivo. So, 12 C was regarded as the optimal nanobody. 12 C CAR-NK cells and IL-15
Taken together, the fourth-generation nanobody-derived anti-CD5 CAR-NK cells may be a promising therapeutic against T-cell malignancies. | [
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] | 2024-10-27 | 75 | 39462383 | [
"T cells",
"malignant T cells",
"allogeneic T cells",
"CD5 CAR-NK cells",
"CAR",
"5D CAR-NK cells",
"5D CAR-T cells",
"CAR-NK cells",
"nanobody",
"CAR therapy",
"CD5",
"T-cell malignancies",
"B-cell malignancies",
"Anti-CD5-D3 nanobody",
"the second-generation CD5 CAR-T cells",
"the fourth-generation nanobody-derived anti-CD5 CAR-NK cells",
"optimal stability",
"superior cytotoxic activity",
"12 C CAR-NK cells",
"Chimeric antigen receptor",
"phage display technology",
"CAR-T",
"antitumor potential",
"high affinity",
"fourth-generation CAR plasmids",
"12 C.b CAR-T cells",
"small size",
"The nanobody-based CAR structures",
"natural killer (NK) cells",
"much attention"
] | [
"CD5",
"Chimeric antigen receptor",
"Nature killer cells",
"T-cell malignancies"
] | 0 | 10.1186/s40164-024-00577-5 | [
"Zu",
"Ren",
"Zhang",
"Su",
"Lu",
"Song",
"Zhou"
] | [
"Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan, 450008, China.",
"Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.",
"Shenzhen Pregene Biopharma Company, Ltd, Shenzhen, Guangdong, 518118, China.",
"Shenzhen Pregene Biopharma Company, Ltd, Shenzhen, Guangdong, 518118, China.",
"Shenzhen Pregene Biopharma Company, Ltd, Shenzhen, Guangdong, 518118, China.",
"Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China. [email protected].",
"Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan, 450008, China. [email protected]."
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39461755 | 319 | Breakthroughs in synthetic controlling strategies for precision in CAR-T therapy. | Chimeric antigen receptors (CAR) are synthetic receptors engineered to target a user-defined antigen. They comprise an extracellular single-chain variable fragment for target recognition and intracellular signalling domains commonly derived from immune cells. CAR-T cells have proven to be successful in therapy of some cancers. CAR-T cells are activated upon antigen-priming and subsequent intracellular signalling. However, tonic signalling in CAR-T cells remains a challenge in developing CAR-T therapeutics of high efficacy as it causes early T-cell exhaustion, limiting therapeutic persistence. Moreover, a poor choice of target antigen leads to off-target cytotoxicity, often hampering the host's survival. In addition, conventional methods of delivering CAR gene circuits utilise viral vectors, such as lentiviruses and retroviruses, which insert the CAR gene circuits into transcriptionally active sites in the genome. This increases the risks of malignant transformation due to improper genome integration. Optimisation in CAR-T engineering, from the architecture of CAR gene circuits to the structure of CAR and the behaviour of CAR-T cells, is paramount to ensure high efficacy, persistence, and precision in CAR-T therapy. This review provides insights into engineering CAR-T cells for precision in cancer therapy by highlighting the key strategies recently developed to optimise the function and efficiency of CARs. The delivery method of CAR gene circuits, circuit and structural modification of CAR, T-cell phenotype manipulation and T-cell arming will be discussed to accentuate their interplay in regulating CAR-T therapy's safety, precision, and efficacy. | [
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] | 2024-10-27 | 1 | 39461755 | [
"CAR gene circuits",
"CAR",
"CARs",
"immune cells",
"target antigen",
"CAR-T cells",
"engineering CAR-T cells",
"Chimeric antigen receptors",
"CAR-T therapy",
"circuit",
"intracellular signalling domains",
"target recognition",
"early T-cell exhaustion",
"CAR-T therapeutics",
"T-cell phenotype manipulation",
"high efficacy",
"T-cell arming",
"cancer therapy",
"malignant transformation",
"improper genome integration",
"target",
"the CAR gene circuits",
"subsequent intracellular signalling",
"therapy",
"CAR-T therapys safety",
"synthetic receptors",
"CAR-T engineering",
"conventional methods",
"viral vectors",
"therapeutic persistence"
] | [
"Cytotoxicity",
"Dual-targeting",
"Lipid nanoparticles",
"MRNA vaccine",
"Naïve T cell",
"Precision medicine",
"Stem cell memory T cell",
"T-cell arming",
"T-cell phenotype",
"Therapeutic efficacy"
] | 0 | 10.1016/bs.pmbts.2024.02.002 | [
"Tang",
"Sugimura"
] | [
"School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China.",
"School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China; Centre for Translational Stem Cell Biology, Hong Kong SAR, China. Electronic address: [email protected]."
] | [
"39461755"
] | [] | 8.515878 | 4.538621 |
39460647 | 320 | In Vitro Assessment of Thermo-Responsive Scaffold as a 3D Synthetic Matrix for CAR-T Potency Testing Against Glioblastoma Spheroids. | Chimeric antigen receptor (CAR) T cell immunotherapy has demonstrated exceptional efficacy against hematological malignancies, but notably less against solid tumors. To overcome this limitation, it is critical to investigate antitumor CAR-T cell potency in synthetic 3D microenvironments that can simulate the physical barriers presented by solid tumors. The overall goal of this study was the preliminary assessment of a synthetic thermo-responsive material as a substrate for in vitro co-cultures of anti-disialoganglioside (GD2) CAR-T cells and patient-derived glioblastoma (GBM) spheroids. Independent co-culture experiments demonstrated that the encapsulation process did not adversely affect the cell cycle progression of glioma stem cells (GSCs) or CAR-T cells. GSC spheroids grew over time within the terpolymer scaffold, when seeded in the same ratio as the suspension control. Co-cultures of CAR-T cells in suspension with hydrogel-encapsulated GSC spheroids demonstrated that CAR-T cells could migrate through the hydrogel and target the encapsulated GSC spheroids. CAR-T cells killed approximately 80% of encapsulated GSCs, while maintaining effective CD4:CD8 T cell ratios and secreting inflammatory cytokines after interacting with GD2-expressing GSCs. Importantly, the scaffolds also facilitated cell harvesting for downstream cellular analysis. This study demonstrated that a synthetic 3D terpolymer hydrogel can serve as an artificial scaffold to investigate cellular immunotherapeutic potency against solid tumors. | [
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] | 2024-10-26 | 1 | 39460647 | [
"T cell immunotherapy",
"CD8 T cell ratios",
"cell harvesting",
"glioma stem cells",
"Independent co-culture experiments",
"antitumor CAR-T cell potency",
"terpolymer hydrogel",
"CAR-T cells",
"GSC spheroids",
"synthetic 3D microenvironments",
"encapsulated GSCs",
"CAR",
"cellular immunotherapeutic potency",
"solid tumors",
"-",
"downstream cellular analysis",
"the cell cycle progression",
"hydrogel-encapsulated GSC spheroids",
"a synthetic 3D terpolymer hydrogel",
"inflammatory cytokines",
"-disialoganglioside (GD2) CAR-T cells",
"exceptional efficacy",
"effective CD4",
"GSC",
"hematological malignancies",
"Chimeric antigen receptor",
"the encapsulated GSC spheroids",
"co",
"suspension",
"cultures"
] | [
"biomaterials",
"immunotherapy",
"potency assays"
] | 0 | 10.1002/jbm.a.37823 | [
"Lizana-Vasquez",
"Ramasubramanian",
"Davarzani",
"Cappabianca",
"Saha",
"Karumbaiah",
"Torres-Lugo"
] | [
"Department of Chemical Engineering, University of Puerto Rico-Mayagüez, Mayagüez, Puerto Rico, USA.",
"Regenerative Bioscience Center, University of Georgia, Athens, Georgia, USA.\nEdgar L. Rhodes Center for Animal and Dairy Science, College of Agriculture and Environmental Science, University of Georgia, Athens, Georgia, USA.",
"Regenerative Bioscience Center, University of Georgia, Athens, Georgia, USA.\nSchool of Electrical and Computer Engineering, University of Georgia, Athens, Georgia, USA.",
"Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin, USA.",
"Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin, USA.",
"Regenerative Bioscience Center, University of Georgia, Athens, Georgia, USA.\nEdgar L. Rhodes Center for Animal and Dairy Science, College of Agriculture and Environmental Science, University of Georgia, Athens, Georgia, USA.\nDivision of Neuroscience, Biomedical and Translational Sciences Institute, University of Georgia, Athens, Georgia, USA.",
"Department of Chemical Engineering, University of Puerto Rico-Mayagüez, Mayagüez, Puerto Rico, USA."
] | [
"39460647"
] | [] | 9.873814 | 6.997478 |
39458157 | 321 | Impact of Allogeneic Stem Cell Transplant on Safety and Outcomes of Chimeric Antigen Receptor T Cell (CAR-T) Therapy in Patients with Multiple Myeloma (MM). | [
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"CART-Therapy",
"Cellular Therapy",
"GVHD",
"stem cell transplant"
] | 0 | 10.3390/jcm13206207
10.1056/NEJMoa1817226
10.1056/NEJMoa2024850
10.1016/j.clml.2023.08.012
10.1007/s40265-017-0689-1
10.1056/NEJMra1703472
10.1182/hematology.2020000111
10.1038/s41571-019-0184-6
10.1146/annurev-immunol-102119-073227
10.1182/blood-2016-04-703751
10.1016/j.bbmt.2018.12.758
10.1172/JCI126397
10.1016/j.htct.2021.10.460
10.1200/JCO.2021.39.15_suppl.8005
10.3389/fimmu.2022.991092
10.1007/s12185-023-03538-6
10.1186/s13045-019-0758-x
10.3389/fimmu.2022.927153
10.3324/haematol.2022.282316
10.1186/s13045-018-0568-6
10.3390/ijms20061283
10.2991/chi.k.201108.001
10.3389/fimmu.2021.693016
10.3390/cancers14010055
10.1038/s41408-023-00900-z
10.1007/s40487-022-00195-3 | [
"Bangolo",
"Amoozgar",
"Zhang",
"Nagesh",
"Sekhon",
"Weissman",
"Vesole",
"Phull",
"Donato",
"Biran",
"Siegel",
"Parmar"
] | [
"Department of Hematology and Oncology, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ 07601, USA.",
"Department of Hematology and Oncology, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ 07601, USA.",
"Department of Hematology and Oncology, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ 07601, USA.",
"Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, USA.",
"Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, USA.",
"Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, USA.",
"Division of Myeloma, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ 07601, USA.",
"Division of Myeloma, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ 07601, USA.",
"Division of Bone Marrow Transplant and Cellular Therapy, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ 07601, USA.",
"Division of Myeloma, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ 07601, USA.",
"Division of Myeloma, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ 07601, USA.",
"Division of Myeloma, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ 07601, USA."
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] | [] | 32.962627 | 7.511967 |
|
39456909 | 322 | Oncolytic Viruses as Reliable Adjuvants in CAR-T Cell Therapy for Solid Tumors. | Although impactful scientific advancements have recently been made in cancer therapy, there remains an opportunity for future improvements. Immunotherapy is perhaps one of the most cutting-edge categories of therapies demonstrating potential in the clinical setting. Genetically engineered T cells express chimeric antigen receptors (CARs), which can detect signals expressed by the molecules present on the surface of cancer cells, also called tumor-associated antigens (TAAs). Their effectiveness has been extensively demonstrated in hematological cancers; therefore, these results can establish the groundwork for their applications on a wide range of requirements. However, the application of CAR-T cell technology for solid tumors has several challenges, such as the existence of an immune-suppressing tumor microenvironment and/or inadequate tumor infiltration. Consequently, combining therapies such as CAR-T cell technology with other approaches has been proposed. The effectiveness of combining CAR-T cell with oncolytic virus therapy, with either genetically altered or naturally occurring viruses, to target tumor cells is currently under investigation, with several clinical trials being conducted. This narrative review summarizes the current advancements, opportunities, benefits, and limitations in using each therapy alone and their combination. The use of oncolytic viruses offers an opportunity to address the existing challenges of CAR-T cell therapy, which appear in the process of trying to overcome solid tumors, through the combination of their strengths. Additionally, utilizing oncolytic viruses allows researchers to modify the virus, thus enabling the targeted delivery of specific therapeutic agents within the tumor environment. This, in turn, can potentially enhance the cytotoxic effect and therapeutic potential of CAR-T cell technology on solid malignancies, with impactful results in the clinical setting. | [
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"Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania.",
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39455854 | 323 | Leveraging CRISPR gene editing technology to optimize the efficacy, safety and accessibility of CAR T-cell therapy. | Chimeric Antigen Receptor (CAR)-T-cell therapy has revolutionized cancer immune therapy. However, challenges remain including increasing efficacy, reducing adverse events and increasing accessibility. Use of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology can effectively perform various functions such as precise integration, multi-gene editing, and genome-wide functional regulation. Additionally, CRISPR screening using large-scale guide RNA (gRNA) genetic perturbation provides an unbiased approach to understanding mechanisms underlying anti-cancer efficacy of CAR T-cells. Several emerging CRISPR tools with high specificity, controllability and efficiency are useful to modify CAR T-cells and identify new targets. In this review we summarize potential uses of the CRISPR system to improve results of CAR T-cells therapy including optimizing efficacy and safety and, developing universal CAR T-cells. We discuss challenges facing CRISPR gene editing and propose solutions highlighting future research directions in CAR T-cell therapy. | [
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] | 2024-10-26 | 236 | 39455854 | [
"CRISPR gene editing",
"Several emerging CRISPR tools",
"CRISPR",
"anti-cancer efficacy",
"multi-gene editing",
"increasing efficacy",
"CAR T-cells therapy",
"cancer immune therapy",
"efficacy",
"CAR T-cell therapy",
"future research directions",
"CAR T-cells",
"universal CAR T-cells",
"various functions",
"high specificity",
"precise integration",
"potential uses",
"increasing accessibility",
"adverse events",
"Chimeric Antigen Receptor (CAR)-T-cell therapy",
"the CRISPR system",
"challenges",
"new targets",
"Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology",
"RNA",
"mechanisms",
"controllability",
"solutions",
"efficiency",
"results"
] | [] | 0 | 10.1038/s41375-024-02444-y
10.1101/2024.03.18.584896v1
10.1101/2024.05.05.592600v1 | [
"Lei",
"Wang",
"Zhang",
"Yang",
"Cao",
"Huang",
"Chen",
"Chen",
"Zhang",
"Wang",
"Xu",
"Gale",
"Wang"
] | [
"The Second School of Clinical Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510145, China.",
"School of Life Sciences, Tsinghua University, Beijing, 100084, China.",
"The Second School of Clinical Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510145, China.",
"The Second School of Clinical Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510145, China.",
"The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510145, China.",
"The Second School of Clinical Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510145, China.",
"The Second School of Clinical Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510145, China.",
"The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510145, China.",
"The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510145, China.",
"State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.",
"State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China. [email protected].",
"Centre for Haematology, Department of Immunology and Inflammation, Imperial College of Science, Technology and Medicine, London, UK. [email protected].",
"Department of Hematology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China. [email protected]."
] | [
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] | [] | 9.434637 | 2.857737 |
39455719 | 324 | Viscoelastic synthetic antigen-presenting cells for augmenting the potency of cancer therapies. | The use of synthetic antigen-presenting cells to activate and expand engineered T cells for the treatment of cancers typically results in therapies that are suboptimal in effectiveness and durability. Here we describe a high-throughput microfluidic system for the fabrication of synthetic cells mimicking the viscoelastic and T-cell-activation properties of antigen-presenting cells. Compared with rigid or elastic microspheres, the synthetic viscoelastic T-cell-activating cells (SynVACs) led to substantial enhancements in the expansion of human CD8 | [
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10.1016/j.stem.2019.08.004 | [
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"Wu",
"Zhu",
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"Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.\nDepartment of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.",
"Section of Restorative Dentistry, School of Dentistry, University of California, Los Angeles, CA, USA.",
"Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.\nDepartment of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.\nDepartment of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.",
"Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA. [email protected].\nDepartment of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA. [email protected].\nMolecular Biology Institute, University of California, Los Angeles, CA, USA. [email protected].\nEli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA. [email protected].\nJonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. [email protected].",
"Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA. [email protected].\nEli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA. [email protected].\nJonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. [email protected]."
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39454410 | 325 | Targeting metabolic pathway enhance CAR-T potency for solid tumor. | Chimeric antigen receptor (CAR) T cells have great potential in cancer therapy, particularly in treating hematologic malignancies. However, their efficacy in solid tumors remains limited, with a significant proportion of patients failing to achieve long-term complete remission. One major challenge is the premature exhaustion of CAR-T cells, often due to insufficient metabolic energy. The survival, function and metabolic adaptation of CAR-T cells are key determinants of their therapeutic efficacy. We explore how targeting metabolic pathways in the tumor microenvironment can enhance CAR-T cell therapy by addressing metabolic competition and immunosuppression that impair CAR-T cell function. Tumors undergo metabolically reprogrammed to meet their rapid proliferation, thereby modulating metabolic pathways in immune cells to promote immunosuppression. The distinct metabolic requirements of tumors and T cells create a competitive environment, affecting the efficacy of CAR-T cell therapy. Recent research on glucose, lipid and amino acid metabolism, along with the interactions between tumor and immune cell metabolism, has revealed that targeting these metabolic processes can enhance antitumor immune responses. Combining metabolic interventions with existing antitumor therapies can fulfill the metabolic demands of immune cells, providing new ideas for tumor immunometabolic therapies. This review discusses the latest advances in the immunometabolic mechanisms underlying tumor immunosuppression, their implications for immunotherapy, and summarizes potential metabolic targets to improve the efficacy of CAR-T therapy. | [
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] | 2024-10-26 | 1 | 39454410 | [
"T cells",
"immune cells",
"tumor immunometabolic therapies",
"tumor immunosuppression",
"metabolic pathways",
"CAR-T cell therapy",
"metabolic adaptation",
"metabolic competition",
"solid tumors",
"potential metabolic targets",
"Tumors",
"tumors",
"existing antitumor therapies",
"CAR-T cell function",
"cancer therapy",
"tumor and immune cell metabolism",
"CAR-T cells",
"antitumor immune responses",
"CAR",
"CAR-T therapy",
"insufficient metabolic energy",
"immunosuppression",
"amino acid",
"great potential",
"new ideas",
"metabolic interventions",
"The distinct metabolic requirements",
"metabolism",
"key determinants",
"Recent research"
] | [
"CAR-T cell therapy",
"Immunotherapy",
"Metabolism reprogramming",
"Tumor microenvironment"
] | 0 | 10.1016/j.intimp.2024.113412 | [
"Li",
"Chen",
"Guo"
] | [
"Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China.",
"Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China. Electronic address: [email protected].",
"Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China. Electronic address: [email protected]."
] | [
"39454410"
] | [] | 10.279501 | 4.956999 |
39453877 | 326 | Adoptive cell therapy in acute myeloid leukemia: the current landscape and emerging strategies. | Efforts to produce adoptive cell therapies in AML have been largely unfruitful, despite the success seen in lymphoid malignancies. Identifying targetable antigens on leukemic cells that are absent on normal progenitor cells remains a major obstacle, as is the hostile tumor microenvironment created by AML blasts. In this review, we summarize the challenges in the development of adoptive cell therapies such as CAR-T, CAR-NK, and TCR-T cells in AML, discussing both autologous and allogeneic therapies. We also discuss methods to address myelotoxicity associated with these therapies, including rapidly switchable CAR platforms and CRISPR-Cas9 genetic engineering of hematopoietic stem cells. Finally, we present the current clinical landscape in these areas, along with future directions in the field. | [
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] | 2024-10-25 | 1 | 39453877 | [
"adoptive cell therapies",
"leukemic cells",
"normal progenitor cells",
"hematopoietic stem cells",
"AML blasts",
"AML",
"future directions",
"TCR-T cells",
"CAR",
"targetable antigens",
"lymphoid malignancies",
"CRISPR-Cas9 genetic engineering",
"myelotoxicity",
"rapidly switchable CAR platforms",
"the current clinical landscape",
"the hostile tumor microenvironment",
"methods",
"both autologous and allogeneic therapies",
"these therapies",
"CAR-NK",
"Efforts",
"CAR-T",
"a major obstacle",
"CRISPR-Cas9",
"these areas",
"the success",
"the development",
"the challenges",
"the field",
"this review"
] | [
"AML",
"CAR-NK",
"CAR-t",
"Cellular therapy"
] | 0 | 10.1080/10428194.2024.2414112 | [
"Tharakan",
"Tremblay",
"Azzi"
] | [
"Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.",
"Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.",
"Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA."
] | [
"39453877"
] | [] | 6.850783 | 7.171211 |
39453747 | 327 | Dual ON/OFF-switch chimeric antigen receptor controlled by two clinically approved drugs. | The ability to remotely control the activity of chimeric antigen receptors (CARs) with small molecules can improve the safety and efficacy of gene-modified T cells. Split ON- or OFF-switch CARs involve the dissociation of tumor-antigen binding from T cell activation (i.e., CD3ζ) on the receptor (R-) and signaling (S-) chains, respectively, that either associate or are disrupted in the presence of a small molecule. Here, we have developed an inducible (i)ON-CAR comprising the anti-apoptotic B cell lymphoma protein 2 protein in the ectodomain of both chains which associate in the presence of venetoclax. We showed that inducible ON (iON)-CAR T cells respond to target tumors cells in the presence of venetoclax or the BH3 mimetic navitoclax in a dose-dependent manner, while there is no impact of the drugs on equivalent second generation-CAR T cells. Within 48 h of venetoclax withdrawal, iON-CAR T cells lose the ability to respond to target tumor cells in vitro as evaluated by Interferon-gamma (IFNγ) production, and they are reliant upon the presence of venetoclax for in vivo activity. Finally, by fusing a degron sequence to the endodomain of the iON-CAR S-chain we generated an all-in-one ON/OFF-switch CAR, the iONØ-CAR, down-regulated by lenalidomide within 4 to 6 for functionally inactive T cells (no IFNγ production) within 24 h. We propose that our remote-control CAR designs can reduce toxicity in the clinic. Moreover, the periodic rest of iON and iONØ-CAR T cells may alleviate exhaustion and hence augment persistence and long-term tumor control in patients. | [
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] | [
"T cell",
"cancer",
"chimeric antigen receptor",
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] | 0 | 10.1073/pnas.2405085121 | [
"Giordano Attianese",
"Shui",
"Cribioli",
"Triboulet",
"Scheller",
"Hafezi",
"Reichenbach",
"Gainza",
"Georgeon",
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] | [
"Ludwig Institute for Cancer Research Lausanne, Department of Oncology, University of Lausanne and Lausanne University Hospital, Lausanne 1011, Switzerland.",
"Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne 1011, Switzerland.\nSwiss Institute of Bioinformatics, Lausanne 1011, Switzerland.",
"Ludwig Institute for Cancer Research Lausanne, Department of Oncology, University of Lausanne and Lausanne University Hospital, Lausanne 1011, Switzerland.",
"Ludwig Institute for Cancer Research Lausanne, Department of Oncology, University of Lausanne and Lausanne University Hospital, Lausanne 1011, Switzerland.",
"Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne 1011, Switzerland.\nSwiss Institute of Bioinformatics, Lausanne 1011, Switzerland.",
"Ludwig Institute for Cancer Research Lausanne, Department of Oncology, University of Lausanne and Lausanne University Hospital, Lausanne 1011, Switzerland.",
"Ludwig Institute for Cancer Research Lausanne, Department of Oncology, University of Lausanne and Lausanne University Hospital, Lausanne 1011, Switzerland.",
"Ludwig Institute for Cancer Research Lausanne, Department of Oncology, University of Lausanne and Lausanne University Hospital, Lausanne 1011, Switzerland.\nSwiss Institute of Bioinformatics, Lausanne 1011, Switzerland.",
"Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne 1011, Switzerland.\nSwiss Institute of Bioinformatics, Lausanne 1011, Switzerland.",
"Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne 1011, Switzerland.\nSwiss Institute of Bioinformatics, Lausanne 1011, Switzerland.",
"Ludwig Institute for Cancer Research Lausanne, Department of Oncology, University of Lausanne and Lausanne University Hospital, Lausanne 1011, Switzerland."
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39453574 | 328 | Design and development of dual targeting CAR protein for the development of CAR T-cell therapy against KRAS mutated pancreatic ductal adenocarcinoma using computational approaches. | Mutant KRAS promotes the proliferation, metastasis, and aggressiveness of various cancers including pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and colorectal adenocarcinoma (CRC) respectively. Mutant KRAS therapeutics are limited, while Sotorasib and Adagrasib were the only FDA-approved drugs for the treatment of KRAS | [
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] | 2024-10-25 | 73 | 39453574 | [
"non-small cell lung cancer",
"pancreatic ductal adenocarcinoma",
"Mutant KRAS therapeutics",
"various cancers",
"Mutant KRAS",
"colorectal adenocarcinoma",
"KRAS",
"FDA",
"Adagrasib",
"Sotorasib",
"metastasis",
"aggressiveness",
"NSCLC",
"PDAC",
"the only FDA-approved drugs",
"CRC",
"the proliferation",
"the treatment"
] | [
"CAR",
"CAR T-cell therapy",
"Immunotherapy",
"KRAS",
"Precision medicine",
"Therapeutics"
] | 0 | 10.1007/s12672-024-01455-6 | [
"Ramalingam",
"Premkumar",
"Sundararajan",
"Hussain",
"Arumugam"
] | [
"Protein Engineering Lab, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India.",
"Integrative Multiomics Lab, School of Bio-Sciences & Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India.",
"Integrative Multiomics Lab, School of Bio-Sciences & Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India.",
"Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, Uttarakhand, 248007, India.",
"Protein Engineering Lab, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India. [email protected]."
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] | [] | 10.112724 | 5.648125 |
39450490 | 329 | Chimeric antigen receptor T-cell therapy in patients with malignant glioma-From neuroimmunology to clinical trial design considerations. | Clinical trials evaluating chimeric antigen receptor (CAR) T-cell therapy in patients with malignant gliomas have shown some early promise in pediatric and adult patients. However, the long-term benefits and safety for patients remain to be established. The ultimate success of CAR T-cell therapy for malignant glioma will require the integration of an in-depth understanding of the immunology of the central nervous system (CNS) parenchyma with strategies to overcome the paucity and heterogeneous expression of glioma-specific antigens. We also need to address the cold (immunosuppressive) microenvironment, exhaustion of the CAR T-cells, as well as local and systemic immunosuppression. Here, we discuss the basics and scientific considerations for CAR T-cell therapies and highlight recent clinical trials. To help identify optimal CAR T-cell administration routes, we summarize our current understanding of CNS immunology and T-cell homing to the CNS. We also discuss challenges and opportunities related to clinical trial design and patient safety/monitoring. Finally, we provide our perspective on future prospects in CAR T-cell therapy for malignant gliomas by discussing combinations and novel engineering strategies to overcome immuno-regulatory mechanisms. We hope this review will serve as a basis for advancing the field in a multiple discipline-based and collaborative manner. | [
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] | 2024-10-25 | 1 | 39450490 | [
"malignant glioma",
"malignant gliomas",
"CAR T-cell therapies",
"CAR T-cell therapy",
"clinical trial design",
"recent clinical trials",
"Clinical trials",
"optimal CAR T-cell administration routes",
"novel engineering strategies",
"CAR) T-cell therapy",
"CNS immunology",
"chimeric antigen receptor",
"patients",
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"T-cell",
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] | [
"T lymphocytes",
"chimeric antigen receptor (CAR)",
"clinical trial",
"geneTherapy",
"malignant glioma"
] | 0 | 10.1093/neuonc/noae203 | [
"Gallus",
"Young",
"Cook Quackenbush",
"Khasraw",
"de Groot",
"Okada"
] | [
"Department of Neurological Surgery, Unversity of California San Fracisco, San Francisco, California, USA.",
"Department of Neurological Surgery, Unversity of California San Fracisco, San Francisco, California, USA.",
"The Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA.",
"The Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA.",
"Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA.\nDepartment of Neurological Surgery, Unversity of California San Fracisco, San Francisco, California, USA.",
"The Parker Institute for Cancer Immunotherapy, San Francisco, California, USA.\nHelen Diller Family Comprehensive Cancer Center, San Francisco, California, USA.\nDepartment of Neurological Surgery, Unversity of California San Fracisco, San Francisco, California, USA."
] | [
"39450490"
] | [] | 9.84411 | 7.259133 |
39450161 | 330 | Modified Dendritic cell-based T-cell expansion protocol and single-cell multi-omics allow for the selection of the most expanded and | Adoptive cell therapy using TCR-engineered T-cells is one of the most effective strategies against tumor cells. The TCR T-cell approach has been well tested against a variety of blood neoplasms but is yet to be deeply tested against solid tumors. Among solid tumors, cancer-testis antigens are the most prominent targets for tumor-specific therapy, as they are usually found on cells that lie behind blood-tissue barriers.
We have employed a novel efficient protocol for MAGE-A3-specific T-cell clonal expansion, performed single-cell multi-omic analysis of the expanded T-cells via BD Rhapsody, engineered a selected T-cell receptor into a lentiviral construct, and tested it in an
We have observed a 191-fold increase in the MAGE-A3-specific T-cell abundance, obtained a dominant T-cell receptor via single-cell multi-omic BD Rhapsody data analysis in the TCRscape bioinformatics tool, and observed potent cytotoxicity of the dominant-clonotype transduced TCR T-cells against a MAGE-A3-positive tumor. We have demonstrated the efficiency of our T-cell enrichment protocol in obtaining potent anti-tumor T-cells and their T-cell receptors, especially when paired with the modern single-cell analysis methods. | [
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"Laboratory of Molecular Immunology, Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia.",
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"Laboratory of Molecular Immunology, Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia.",
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39450160 | 331 | A novel strategy of co-expressing CXCR5 and IL-7 enhances CAR-T cell effectiveness in osteosarcoma. | Solid tumors are characterized by a low blood supply, complex stromal architecture, and immunosuppressive milieu, which inhibit CAR-T cell entry and survival. CXCR5 has previously been employed to increase CAR-T cell infiltration into CXCL13+ cancers. On the other hand, IL-7 improves the survival and persistence of T cells inside a solid tumor milieu.
We constructed a novel NKG2D-based CAR (C5/IL7-CAR) that co-expressed CXCR5 and IL-7. The human osteosarcoma cell lines U-2 OS, 143B, and Mg63 highly expressed MICA/B and CXCL13, thus presenting a perfect avenue for the present study.
Novel CAR-T cells are superior in their activation, degranulation, and cytokine release competence, hence lysing more target cells than conventional CAR. Furthermore, CXCR5 and IL-7 co-expression decreased the expression of PD-1, TIM-3, and TIGIT and increased Bcl-2 expression. Novel CAR-T cells show enhanced proliferation and differentiation towards the stem cell memory T cell phenotype. C5/IL7-CAR-T cells outperformed conventional CAR-T in eradicating osteosarcoma in mouse models and displayed better survival. Additionally, CXCR5 and IL-7 co-expression enhanced CAR-T cell numbers, cytokine release, and survival in implanted tumor tissues compared to conventional CAR-T cells. Mechanistically, C5/IL7-CAR-T cells displayed enhanced STAT5 signaling.
These findings highlight the potential of CXCR5 and IL-7 co-expression to improve CAR-T cell therapy efficacy against osteosarcoma. | [
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] | 2024-10-25 | 40 | 39450160 | [
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] | [
"CAR-T therapy",
"CXCR5",
"IL-7",
"T cell migration",
"osteosarcoma",
"tumor microenvironment"
] | 0 | 10.3389/fimmu.2024.1462076
10.1111/sji.12741
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10.1038/nri2970 | [
"Hui",
"Farooq",
"Chen",
"Ajmal",
"Ren",
"Xue",
"Ji",
"Du",
"Wu",
"Jiang"
] | [
"Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.",
"Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.\nThe First Dongguan Affiliated Hospital, Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Guangdong Medical University, Dongguan, China.",
"Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.",
"Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.\nThe First Dongguan Affiliated Hospital, Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Guangdong Medical University, Dongguan, China.",
"Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.\nCollege of Life Science, Xinjiang Normal University, Urumqi, China.",
"Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.",
"Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.",
"Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.",
"Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.",
"Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China."
] | [
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39448032 | 332 | Shift from Widespread to Tailored Antifungal Prophylaxis in Lymphoma Patients Treated with CD19 CAR T Cell Therapy: Results from a Large Retrospective Cohort. | Patients undergoing CD19 chimeric antigen receptor (CAR)-T cell therapy exhibit multiple immune deficits that may increase their susceptibility to infections. Invasive fungal infections (IFIs) are life-threatening events in the setting of hematologic diseases. However, there is ongoing debate regarding the optimal role and duration of antifungal prophylaxis in this specific patient population. The objective of this study was to provide a comprehensive overview of the evolution of IFI prophylactic strategies over time and to assess IFI incidence rates in a cohort of patients with relapsed or refractory (R/R) lymphoma treated with CAR-T cell therapy. A single-center retrospective study was conducted on a cohort of patients with R/R B cell lymphoma treated with CD19 CAR-T cell therapy between April 2016 and March 2023. Group A (April 2016-August 2020) consisted of patients primarily treated with fluconazole, irrespective of their individual IFI risk profile. In Group B (September 2020-March 2023) antifungal prophylaxis was recommended only for high-risk patients. Overall, 330 patients were included. Antifungal prophylaxis was prescribed to 119/142 (84%) patients in Group A and 58/188 (31%) in Group B (P < .001). Anti-mold azoles were prescribed to 8 (5.6%) patients in Group A and 21 (11.2%) patients in Group B. In Group A, 42 (29%) patients were switched to another antifungal, 9 (21%) because of toxicity, with 6 cases of transaminitis and 3 cases of prolonged QTc. In Group B, 21 (11.2%) patients were switched to the antifungal drug, mainly from fluconazole or micafungin to a mold-active agent following revised guidelines. No difference was found in liver toxicity between the two groups at infusion, day 10, and day 30. No significant differences were observed between the groups. IFIs following CAR-T cell therapy were rare, with 1 case of cryptococcal meningoencephalitis in group A (.7%) and 1 case of invasive aspergillosis in Group B (.5%), both occurring in patients on micafungin prophylaxis. In this large single-center cohort of patients with R/R lymphoma treated with CAR-T cells, we show that individualized prophylaxis, alongside careful management of CAR-T cell-related toxicities such as CRS, was associated with a very low IFI rate, avoiding the risk of unnecessary toxicities, drug-drug interactions, and high costs. | [
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] | 2024-10-25 | 1 | 39448032 | [
"Patients",
"patients",
"CAR)-T cell therapy",
"antifungal prophylaxis",
"Group B",
"micafungin prophylaxis",
"Group A",
"IFI incidence rates",
"individualized prophylaxis",
"liver toxicity",
"unnecessary toxicities",
"IFI prophylactic strategies",
"R/R B cell",
"Antifungal prophylaxis",
"group A",
"toxicity",
"CD19 CAR-T cell therapy",
"IFI",
"Group B.",
"CAR-T cell therapy",
"Invasive fungal infections",
"CD19 chimeric antigen receptor",
"multiple immune deficits",
"high-risk patients",
"CAR-T cells",
"Anti-mold azoles",
"invasive aspergillosis",
"R/R",
"ongoing debate",
"their individual IFI risk profile"
] | [
"Antifungal prophylaxis",
"CAR-T cell toxicity",
"Invasive fungal infections",
"R/R B cell lymphoma",
"Risk stratification"
] | 0 | 10.1016/j.jtct.2024.10.010 | [
"Melica",
"Luna de Abia",
"Shah",
"Devlin",
"Corona",
"Fein",
"Dahi",
"Giralt",
"Lin",
"Palomba",
"Parascondola",
"Park",
"Salles",
"Saldia",
"Scordo",
"Shouval",
"Perales",
"Seo"
] | [
"Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Infectious Diseases and Clinical Immunology, Henri Mondor Hospital, APHP, Creteil, France.",
"Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Adult Bone Marrow Transplantation, Hospital Universitario Ramón y Cajal, Madrid, Spain.",
"Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.",
"Department of Medicine, Weill Cornell Medical College, New York, New York; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.",
"Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, New York.",
"Department of Medicine, Weill Cornell Medical College, New York, New York.",
"Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.",
"Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.",
"Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.",
"Department of Medicine, Weill Cornell Medical College, New York, New York; Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York.",
"Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, New York.",
"Department of Medicine, Weill Cornell Medical College, New York, New York; Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, New York.",
"Department of Medicine, Weill Cornell Medical College, New York, New York; Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York.",
"Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, New York.",
"Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.",
"Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.",
"Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.",
"Department of Medicine, Weill Cornell Medical College, New York, New York; Department of Medicine, Infectious Disease Service, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address: [email protected]."
] | [
"39448032"
] | [] | 6.033886 | 4.206091 |
39447569 | 333 | Anti-CD19 CAR-T cells are effective in severe idiopathic Lambert-Eaton myasthenic syndrome. | Lambert-Eaton myasthenic syndrome (LEMS) is an autoantibody-mediated disease of the neuromuscular junction characterized by muscular weakness. Autoantibodies to presynaptic P/Q-type voltage-gated calcium channels (VGCCs) induce defective neuromuscular function. In severe cases, current immunosuppressive and immunomodulatory treatment strategies are often insufficient. First reports show beneficial effects of anti-CD19 chimeric antigen receptor (CAR)-T cell therapy in patients with autoantibody-mediated myasthenia gravis. We report a patient with isolated idiopathic LEMS treated with autologous anti-CD19-CAR-T cells. In this patient, CAR-T infusion leads to expansion of predominantly CD4 | [
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10.1126/sciadv.adg3919 | [
"Wickel",
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"Borie",
"Dudziak",
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] | [
"Section Translational Neuroimmunology, Department of Neurology, Jena University Hospital, Jena, Germany.",
"Klinik für Innere Medizin II, Hematology/Oncology, Jena University Hospital, Jena, Germany; Comprehensive Cancer Center Central Germany, Campus Jena, Jena, Germany.",
"Institute for Transfusion Medicine, University Hospital Jena, Jena, Germany.",
"Klinik für Innere Medizin II, Hematology/Oncology, Jena University Hospital, Jena, Germany.",
"Kyverna Therapeutics, Emeryville, CA, USA.",
"Comprehensive Cancer Center Central Germany, Campus Jena, Jena, Germany; Institute of Immunology, Jena University Hospital, Jena, Germany; Laboratory of Dendritic Cell Biology, Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.",
"Klinik für Innere Medizin II, Hematology/Oncology, Jena University Hospital, Jena, Germany; Comprehensive Cancer Center Central Germany, Campus Jena, Jena, Germany.",
"Laboratory of Dendritic Cell Biology, Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany; Department of Transfusion Medicine and Hemostaseology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.",
"Section Translational Neuroimmunology, Department of Neurology, Jena University Hospital, Jena, Germany. Electronic address: [email protected]."
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39445844 | 334 | Deciphering the landscape of triple negative breast cancer from microenvironment dynamics and molecular insights to biomarker analysis and therapeutic modalities. | Triple negative breast cancer (TNBC) displays a notable challenge in clinical oncology due to its invasive nature which is attributed to the absence of progesterone receptor (PR), estrogen receptor (ER), and human epidermal growth factor receptor (HER-2). The heterogenous tumor microenvironment (TME) of TNBC is composed of diverse constituents that intricately interact to evade immune response and facilitate cancer progression and metastasis. Based on molecular gene expression, TNBC is classified into four molecular subtypes: basal-like (BL1 and BL2), luminal androgen receptor (LAR), immunomodulatory (IM), and mesenchymal. TNBC is an aggressive histological variant with adverse prognosis and poor therapeutic response. The lack of response in most of the TNBC patients could be attributed to the heterogeneity of the disease, highlighting the need for more effective treatments and reliable prognostic biomarkers. Targeting certain signaling pathways and their components has emerged as a promising therapeutic strategy for improving patient outcomes. In this review, we have summarized the interactions among various components of the dynamic TME in TNBC and discussed the classification of its molecular subtypes. Moreover, the purpose of this review is to compile and provide an overview of the most recent data about recently discovered novel TNBC biomarkers and targeted therapeutics that have proven successful in treating metastatic TNBC. The emergence of novel therapeutic strategies such as chemoimmunotherapy, chimeric antigen receptor (CAR)-T cells-based immunotherapy, phytometabolites-mediated natural therapy, photodynamic and photothermal approaches have made a significant positive impact and have paved the way for more effective interventions. | [
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] | 2024-10-24 | 1 | 39445844 | [
"metastatic TNBC",
"TNBC",
"luminal androgen receptor",
"chimeric antigen receptor",
"progesterone receptor",
"poor therapeutic response",
"novel therapeutic strategies",
"facilitate cancer progression",
"immune response",
"Triple negative breast cancer",
"various components",
"molecular gene expression",
"reliable prognostic biomarkers",
"targeted therapeutics",
"response",
"certain signaling pathways",
"TME",
"adverse prognosis",
"clinical oncology",
"diverse constituents",
"the TNBC patients",
"a promising therapeutic strategy",
"patient outcomes",
"recently discovered novel TNBC biomarkers",
"LAR",
"phytometabolites-mediated natural therapy",
"ER",
"BL2",
"chemoimmunotherapy",
"PR"
] | [
"CAR‐T cells",
"TNBC",
"chemoimmunotherapy",
"oncogenic signaling",
"prognostic biomarkers"
] | 0 | 10.1002/med.22090 | [
"Tiwari",
"Singh",
"Sharma",
"Gupta",
"Verma",
"Chattopadhaya",
"Kumar",
"Agarwal",
"Kumar",
"Gupta",
"Gautam"
] | [
"Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India.",
"Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India.",
"Department of General Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India.",
"Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India.",
"Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India.",
"Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India.",
"Department of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi, Uttar Pradesh, India.",
"Department of Obstetrics and Gynaecology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India.",
"Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India.",
"Department of General Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India.",
"Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India."
] | [
"39445844"
] | [] | 10.486533 | 5.293338 |
39445067 | 335 | Enhanced tumor control and survival in preclinical models with adoptive cell therapy preceded by low-dose radiotherapy. | Effective infiltration of chimeric antigen receptor T (CAR-T) cells into solid tumors is critical for achieving a robust antitumor response and improving therapeutic outcomes. While CAR-T cell therapies have succeeded in hematologic malignancies, their efficacy in solid tumors remains limited due to poor tumor penetration and an immunosuppressive tumor microenvironment. This study aimed to evaluate the potential of low-dose radiotherapy (LDRT) administered before T-cell therapy to enhance the antitumor effect by promoting CAR-T cell infiltration. We hypothesized that combining LDRT with T-cell therapy would improve tumor control and survival compared to either treatment alone.
We investigated this hypothesis using two NSG mouse models bearing GSU or CAPAN-2 solid tumors. The mice were treated with engineered CAR-T cells targeting guanyl cyclase-C (GCC) or mesothelin as monotherapy or in combination with LDRT. Additionally, we extended this approach to a C57BL/6 mouse model implanted with MC38-gp100+ cells, followed by adoptive transfer of pmel+ T cells before and after LDRT. Tumor growth and survival outcomes were monitored in all models. Furthermore, we employed atomic force microscopy (AFM) in a small cohort to assess the effects of radiotherapy on tumor stiffness and plasticity, exploring the role of tumor nanomechanics as a potential biomarker for treatment efficacy.
Our results demonstrated enhanced tumor control and prolonged survival in mice treated with LDRT followed by T-cell therapy across all models. The combination of LDRT with CAR-T or pmel+ T-cell therapy led to superior tumor suppression and survival compared to monotherapy, highlighting the synergistic impact of the combined approach. Additionally, AFM analysis revealed significant changes in tumor stiffness and plasticity in response to LDRT, suggesting that the nanomechanical properties of the tumor may be predictive of therapeutic response.
The findings of this study highlight the transformative potential of incorporating LDRT as a precursor to adoptive T-cell therapy in solid tumors. By promoting CAR-T and pmel+ T-cell infiltration into the tumor microenvironment, LDRT enhanced tumor control and improved survival outcomes, offering a promising strategy to overcome the challenges associated with CAR-T therapy in solid tumors. Additionally, the changes in tumor nanomechanics observed through AFM suggest that tumor stiffness and plasticity could be biomarkers for predicting treatment outcomes. These results support further investigation into the clinical application of this combined approach to improve the efficacy of cell-based therapies in patients with solid tumors. | [
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"Department of Radiation Oncology-Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.",
"Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.",
"Department of Radiation Oncology-Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.",
"Takeda Development Centers Americas, Inc, Lexington, MA, United States.",
"ARTIDIS AG, Basel, Switzerland.",
"Department of Radiation Oncology-Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.",
"ARTIDIS AG, Basel, Switzerland.",
"Department of Radiation Oncology-Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.",
"Department of Radiation Oncology-Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.",
"Takeda Development Centers Americas, Inc, Lexington, MA, United States.",
"Department of Radiation Oncology-Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.",
"Department of Radiation Oncology-Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.",
"Department of Radiation Oncology-Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.",
"Medical College of Wisconsin, Milwaukee, WI, United States.",
"Department of Radiation Oncology-Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.",
"Department of Radiation Oncology-Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.",
"Department of Radiation Oncology-Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.",
"Department of Radiation Oncology-Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.",
"Department of Radiation Oncology-Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.",
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"Department of Radiation Oncology-Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.",
"Department of Radiation Oncology-Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.",
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"ARTIDIS AG, Basel, Switzerland.",
"ARTIDIS AG, Basel, Switzerland.",
"Takeda Development Centers Americas, Inc, Lexington, MA, United States.",
"Department of Radiation Oncology-Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States."
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39445021 | 336 | Application of novel CAR technologies to improve treatment of autoimmune disease. | Chimeric antigen receptor (CAR) T cell therapy has become an important treatment for hematological cancers, and its success has spurred research into CAR T cell therapies for other diseases, including solid tumor cancers and autoimmune diseases. Notably, the development of CAR-based treatments for autoimmune diseases has shown great progress recently. Clinical trials for anti-CD19 and anti-BCMA CAR T cells in treating severe B cell-mediated autoimmune diseases, like systemic lupus erythematosus (SLE), have shown lasting remission thus far. CAR T cells targeting autoreactive T cells are beginning clinical trials for treating T cell mediated autoimmune diseases. Chimeric autoantigen receptor (CAAR) T cells specifically target and eliminate only autoreactive B cells, and they have shown promise in treating mucosal pemphigus vulgaris and MuSK myasthenia gravis. Regulatory CAR T cells have also been developed, which show potential in altering autoimmune affected areas by creating a protective barrier as well as helping decrease inflammation. These new treatments are only the beginning of potential CAR T cell applications in treating autoimmune disease. Novel CAR technologies have been developed that increase the safety, potency, specificity, and efficacy of CAR T cell therapy. Applying these novel modifications to autoimmune CARs has the potential to enhance the efficacy and applicability of CAR therapies to autoimmune disease. This review will detail several recently developed CAR technologies and discuss how their application to autoimmune disease will improve this emerging field. These include logic-gated CARs, soluble protein-secreting CARs, and modular CARs that enable CAR T cell therapies to be more specific, reach a wider span of target cells, be safer for patients, and give a more potent cytotoxic response. Applying these novel CAR technologies to the treatment of autoimmune diseases has the potential to revolutionize this growing application of CAR T cell therapies. | [
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39443955 | 337 | Membrane-bound IL-7 immobilized by the CD8 transmembrane region improves efficacy of CD19 CAR-T cell therapy. | Enhancing the efficacy of CD19 CAR-T cell therapy can significantly improve patient outcomes by reducing relapse rates in CD19 + B cell malignancies. Exogenous or transgenic cytokines are often used to boost the expansion and durability of CAR-T cells but pose risks of severe toxicities. A promising approach to address these limitations is to immobilize cytokines on the surface of CAR-T cells using transmembrane (TM) anchor domains. Given IL-7 can enhance T-cell proliferation and antitumor activity, our study developed membrane-bound IL-7 constructs using different TM anchor domains (CD8, CD28 and B7-1). We primarily found that the CD8 TM provided superior anchoring for IL-7 compared to CD28 and B7-1. Moreover, the IL-7 construct with a CD8 TM (IL7/CD8) enhanced naïve T cell proliferation and effector functions, and improved the in vitro and in vivo antitumor activity of CD19 CAR-T cells. Importantly, although IL7/CD8 could promote T-cell proliferation, it did not sustain long-term autonomous expansion, which could ensure the safety of CD19 CAR-T cells expressing IL7/CD8 in clinical applications. Collectively, the IL7/CD8 construct represents a promising strategy for enhancing the therapeutic potential of CD19 CAR-T cell therapy. | [
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] | 2024-10-24 | 7 | 39443955 | [
"CD19 CAR-T cell therapy",
"CD19 CAR-T cells",
"CAR-T cells",
"different TM anchor domains",
"T-cell proliferation",
"enhanced naïve T cell proliferation and effector functions",
"CD8",
"vivo antitumor activity",
"antitumor activity",
"TM",
"CD19 + B cell malignancies",
"superior anchoring",
"relapse rates",
"patient outcomes",
"cytokines",
"the CD8 TM",
"IL-7",
"membrane-bound IL-7 constructs",
"CD28",
"severe toxicities",
"IL7/CD8",
"long-term autonomous expansion",
"clinical applications",
"a CD8 TM (IL7/CD8",
"B7",
"the IL7/CD8 construct",
"transmembrane (TM) anchor domains",
"risks",
"durability",
"Exogenous or transgenic cytokines"
] | [
"CD19 CAR-T",
"Hematologic malignancy",
"Membrane-bound IL-7"
] | 0 | 10.1186/s12943-024-02154-0 | [
"Zhang",
"Liu",
"Li",
"Teng",
"Zhu",
"Zhang",
"Xie",
"Sun",
"Tu",
"Yang",
"Lu"
] | [
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Surgery II, Peking University Cancer Hospital & Institute, Beijing, 100142, China.",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.",
"Key Laboratory of Tropical Translational Medicine of Ministry of Education, The First Affiliated Hospital of Hainan Medical University, Haikou, 571199, China. [email protected].\nThe Department of Medical Oncology, The General Hospital of Ningxia Medical University, Yinchuan, 750004, China. [email protected].",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China. [email protected]."
] | [
"39443955",
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"25695689",
"38191529",
"36350987",
"31959727"
] | [] | 8.027966 | 5.417499 |
39443938 | 338 | CAR-NK cells for gastrointestinal cancer immunotherapy: from bench to bedside. | Gastrointestinal (GI) cancers represent a significant health burden worldwide. Their incidence continues to increase, and their management remains a clinical challenge. Chimeric antigen receptor (CAR) natural killer (NK) cells have emerged as a promising alternative to CAR-T cells for immunotherapy of GI cancers. Notably, CAR-NK cells offer several advantages, including reduced risk of graft-versus-host disease, lower cytokine release syndrome, and the ability to target cancer cells through both CAR-dependent and natural cytotoxic mechanisms.
This review comprehensively discusses the development and applications of CAR-NK cells in the treatment of GI cancers. We explored various sources of NK cells, CAR design strategies, and the current state of CAR-NK cell therapy for GI cancers, highlighting recent preclinical and clinical trials. Additionally, we addressed existing challenges and propose potential strategies to enhance the efficacy and safety of CAR-NK cell therapy.
Our findings highlight the potential of CAR-NK cells to revolutionize GI cancer treatment and pave the way for future clinical applications. | [
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] | [
"CAR-NK cells",
"Combination therapy",
"Gastrointestinal cancers",
"Immunotherapy",
"Tumor microenvironment"
] | 0 | 10.1186/s12943-024-02151-3 | [
"Zhu",
"Xue",
"Jiang",
"Xue"
] | [
"Department of Urinary Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, 110032, P.R. China.",
"China Medical University, Shenyang, Liaoning Province, 110000, P.R. China.",
"Department of Neurosurgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, 110032, P.R. China.",
"Department of Urinary Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, 110032, P.R. China. [email protected]."
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"Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.\nSandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.",
"Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.\nSandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.",
"Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.",
"Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.\nSandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.",
"Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.\nSandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.\nResearch Institute, National Cancer Center, Goyang, Republic of Korea.",
"Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.",
"Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.\nSandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.",
"Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.",
"Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.\nSandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.",
"Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.\nSandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.\nWeill Cornell Graduate School of Medical Sciences, New York, NY, USA.",
"Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.",
"Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.\nHSS Research Institute and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, USA.",
"Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.\nHSS Research Institute and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, USA.",
"Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.",
"Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.\nSandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.",
"Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.\nSandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.",
"Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.\nSandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.",
"Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.",
"Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.",
"Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.",
"Department of Integrated Immunobiology, Duke School of Medicine, Durham, NC, USA.\nDuke Cancer Institute, Duke School of Medicine, Durham, NC, USA.",
"Department of Anesthesiology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA.\nInstitute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY, USA.\nStony Brook University Pain and Analgesia Research Center (SPARC), Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA.",
"Research Program in Systems Oncology, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.\nFoundation for the Finnish Cancer Institute, Helsinki, Finland.",
"Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.\nSandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.\nDepartments of Integrative Biotechnology and of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon, Republic of Korea.",
"Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA. [email protected].\nSandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. [email protected].\nWeill Cornell Graduate School of Medical Sciences, New York, NY, USA. [email protected]."
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39442586 | 340 | Outcomes with chimeric antigen receptor T-cell therapy in Rheumatological disorders: A systematic review. | Chimeric antigen receptor T cell (CAR-T) therapy is an emerging form of immunotherapy that has recently gained recognition for treating hematological malignancies. This successful utilization of CAR-T therapy has attracted interest in its application in refractory rheumatological diseases. Here, we will review the use of CAR-T therapy in rheumatological diseases.
Per PRISMA guidelines, a comprehensive literature search was performed on PubMed, Cochrane, and ClinicalTrials.gov using keywords for 'CAR-T cell therapy' and 'Rheumatological diseases' from inception to December 9, 2023. After screening 2977 articles, six studies reporting outcomes of CAR-T cell therapies in patients with underlying autoimmune /rheumatological diseases. Descriptive analysis was performed to represent demographics and clinical outcomes.
A total of 101 adult patients from six studies were included in this systematic review. The median age of the participants was 50.8 years (IQR: 14.875), with ages ranging from 18 to 83 years. The included studies comprised 2 case reports, 1 case series, one observational study, and two clinical trials. The studies were conducted globally, including USA, Germany, and China. The underlying rheumatologic conditions were systemic lupus erythematosus (17.8 %), rheumatoid arthritis (23.8 %), myasthenia gravis (13.8 %), neuromyelitis optica (11.9 %), and others (32.7 %). The target of CAR-T therapy included CD-19 in four studies and B cell maturation antigen (BCMA) in two studies. All the patients were on prior therapy, including glucocorticoids and disease-modifying antirheumatic drugs. Follow-up ranged from a month to 1.5 years. Most of the studies reported improvement in the symptoms and decline in serological biomarkers of the underlying disease. The notable outcomes in the included studies were a 100 % response rate in five out of six studies. Grade 1 and 2 cytokine release syndrome (CRS) was observed in five studies. Only one study reported Grade 3 or higher CRS. 2 patients (1.98 %) developed neurotoxicity among the adverse effects.
CAR-T cell therapy is a paradigm shift in managing rheumatologic diseases, with symptomatic improvement and biochemical control of these diseases. Although preliminary evidence indicates promising results, long-term follow-up and prospective clinical trials are needed to establish optimal timing and assess the safety and efficacy of CAR-T immunotherapy. | [
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] | 2024-10-24 | 1 | 39442586 | [
"prior therapy",
"rheumatological diseases",
"refractory rheumatological diseases",
"rheumatologic diseases",
"CAR-T cell therapies",
"B cell maturation antigen",
"CAR-T cell therapy",
"CAR-T therapy",
"clinical outcomes",
"The included studies",
"the included studies",
"symptomatic improvement",
"systemic lupus erythematosus",
"promising results",
"patients",
"Chimeric antigen receptor T cell (CAR-T) therapy",
"higher CRS",
"optimal timing",
"CAR-T immunotherapy",
"one observational study",
"outcomes",
"myasthenia gravis",
"improvement",
"rheumatoid arthritis",
"disease-modifying antirheumatic drugs",
"serological biomarkers",
"neuromyelitis optica",
"preliminary evidence",
"Rheumatological diseases",
"CRS"
] | [
"Chimeric antigen receptor T-cell therapy",
"Outcomes",
"Rheumatological disorders",
"Systemic review"
] | 0 | 10.1016/j.trim.2024.102137 | [
"Zulfiqar",
"Shahzad",
"Amin",
"Vyas",
"Sarfraz",
"Zainab",
"Qasim",
"Kaur",
"Khavandgar",
"Lutfi",
"Hematti",
"McGuirk",
"Mushtaq"
] | [
"Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, United States; Mikael Rayaan Foundation Global Transplantation and Cellular Therapy Consortium, Kansas City, Kansas, United States.",
"Division of Hematology and Oncology, Moffitt Cancer Center, University of South Florida, Tampa, Florida, United States; Mikael Rayaan Foundation Global Transplantation and Cellular Therapy Consortium, Kansas City, Kansas, United States.",
"Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, United States; Mikael Rayaan Foundation Global Transplantation and Cellular Therapy Consortium, Kansas City, Kansas, United States.",
"Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, United States; Mikael Rayaan Foundation Global Transplantation and Cellular Therapy Consortium, Kansas City, Kansas, United States.",
"Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, United States; Mikael Rayaan Foundation Global Transplantation and Cellular Therapy Consortium, Kansas City, Kansas, United States.",
"Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, United States; Mikael Rayaan Foundation Global Transplantation and Cellular Therapy Consortium, Kansas City, Kansas, United States.",
"Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, United States; Mikael Rayaan Foundation Global Transplantation and Cellular Therapy Consortium, Kansas City, Kansas, United States.",
"Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, United States; Mikael Rayaan Foundation Global Transplantation and Cellular Therapy Consortium, Kansas City, Kansas, United States.",
"Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, United States; Mikael Rayaan Foundation Global Transplantation and Cellular Therapy Consortium, Kansas City, Kansas, United States.",
"Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, United States; Mikael Rayaan Foundation Global Transplantation and Cellular Therapy Consortium, Kansas City, Kansas, United States.",
"Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Florida, United States; Mikael Rayaan Foundation Global Transplantation and Cellular Therapy Consortium, Kansas City, Kansas, United States.",
"Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, United States; Mikael Rayaan Foundation Global Transplantation and Cellular Therapy Consortium, Kansas City, Kansas, United States.",
"Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, United States; Mikael Rayaan Foundation Global Transplantation and Cellular Therapy Consortium, Kansas City, Kansas, United States. Electronic address: [email protected]."
] | [
"39442586"
] | [] | 7.490945 | 4.333503 |
39441941 | 341 | Antibiotic-induced loss of gut microbiome metabolic output correlates with clinical responses to CAR T-cell therapy. | Antibiotic-induced microbiome dysbiosis is widespread in oncology, adversely affecting outcomes and side effects of various cancer treatments, including immune checkpoint inhibitors and chimeric antigen receptor T (CAR-T) cell therapies. In this study, we observed that prior exposure to broad-spectrum ABX with extended anaerobic coverage like piperacillin-tazobactam and meropenem was associated with worsened anti-CD19 CAR-T therapy survival outcomes in large B-cell lymphoma patients (n=422), compared to other ABX classes. In a discovery subset of these patients (n=67), we found that the use of these ABX was in turn associated with substantial dysbiosis of gut microbiome function, resulting in significant alterations of the gut and blood metabolome, including microbial effectors such as short-chain fatty acids (SCFAs) and other anionic metabolites, findings that were largely reproduced in an external validation cohort (n=58). Broader evaluation of circulating microbial metabolites revealed reductions in indole and cresol derivatives, as well as trimethylamine N-oxide, in patients who received ABX treatment (discovery n=40, validation n=28). These findings were recapitulated in an immune-competent CAR-T mouse model, where meropenem-induced dysbiosis led to a systemic dysmetabolome and decreased murine anti-CD19 CAR-T efficacy. Furthermore, we demonstrate that SCFAs can enhance the metabolic fitness of CAR-T cells, leading to improved tumor killing capacity. Together, these results suggest that broad-spectrum ABX deplete metabolically active commensals whose metabolites are essential for enhancing CAR-T efficacy, shedding light on the intricate relationship between ABX exposure, microbiome function and their impact on CAR-T cell efficacy. This highlights the potential for modulating the microbiome to augment CAR-T immunotherapy. | [
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] | 2024-10-23 | 1 | 39441941 | [
"ABX treatment",
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"CAR-T cell efficacy",
"gut microbiome function",
"substantial dysbiosis",
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"various cancer treatments",
"worsened anti-CD19 CAR-T therapy survival outcomes",
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"validation n=28",
"significant alterations",
"side effects",
"outcomes",
"Antibiotic-induced microbiome dysbiosis"
] | [] | 0 | 10.1182/blood.2024025366 | [
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] | [
"The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.",
"The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.",
"The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.",
"The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.",
"University Hospital, LMU Munich, Germany.",
"University Clinic Heidelberg, Germany.",
"Weizmann Institute of Science, Rehovot, Israel.",
"German Cancer Research Center (DKFZ), Heidelberg, Germany.",
"German Cancer Research Center (DKFZ), Heidelberg, Germany.",
"The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.",
"The University of Texas MD Anderson Cancer Center, United States.",
"The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.",
"The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.",
"The University of Texas MD Anderson Cancer Center, United States.",
"The University of Texas MD Anderson Cancer Center, United States.",
"The University of Texas MD Anderson Cancer Center, United States.",
"University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States.",
"The University of Texas MD Anderson Cancer Center, United States.",
"The University of Texas MD Anderson Cancer Center, United States.",
"The University of Texas MD Anderson Cancer Center, United States.",
"The University of Texas MD Anderson Cancer Center, United States.",
"The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.",
"The University of Texas MD Anderson Cancer Center, United States.",
"The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.",
"Moffitt Cancer Center, Tampa, Florida, United States.",
"The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.",
"The University of Texas MD Anderson Cancer Center, United States.",
"The University of Texas MD Anderson Cancer Center, United States.",
"Moffitt Cancer Center, Tampa, Florida, United States.",
"Moffitt Cancer Center, Tampa, Florida, United States.",
"Moffitt Cancer Center, Tampa, Florida, United States.",
"Roswell Park Comprehensive Cancer Center, Buffalo, New York, United States.",
"University Clinic Heidelberg, Heidelberg, Germany.",
"University Hospital Heidelberg, Heidelberg, Germany.",
"University Clinic Heidelberg, Germany.",
"The University of Texas MD Anderson Cancer Center, United States.",
"The University of Texas MD Anderson Cancer Center, United States.",
"The University of Texas MD Anderson Cancer Center, United States.",
"The University of Texas MD Anderson Cancer Center, United States.",
"The University of Texas MD Anderson Cancer Center, United States.",
"The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.",
"University Clinic Heidelberg, Germany.",
"University Hospital, LMU Munich, Munich, Germany.",
"The University of Texas MD Anderson Cancer Center, United States.",
"University of Tuebingen, Tuebingen, Germany.",
"Weizmann Institute of Science, Rehovot, Israel.",
"Moffitt Cancer Center, Tampa, Florida, United States.",
"The University of Texas MD Anderson Cancer Center, United States.",
"The University of Texas MD Anderson Cancer Center, United States.",
"The University of Texas MD Anderson Cancer Center, Houston, Texas, United States."
] | [
"39441941"
] | [] | 6.798015 | 4.924522 |
39441641 | 342 | Optogenetically engineered Septin-7 enhances immune cell infiltration of tumor spheroids. | Chimeric antigen receptor T cell therapies have achieved great success in eradicating some liquid tumors, whereas the preclinical results in treating solid tumors have proven less decisive. One of the principal challenges in solid tumor treatment is the physical barrier composed of a dense extracellular matrix, which prevents immune cells from penetrating the tissue to attack intratumoral cancer cells. Here, we improve immune cell infiltration into solid tumors by manipulating septin-7 functions in cells. Using protein allosteric design, we reprogram the three-dimensional structure of septin-7 and insert a blue light-responsive light-oxygen-voltage-sensing domain 2 (LOV2), creating a light-controllable septin-7-LOV2 hybrid protein. Blue light inhibits septin-7 function in live cells, inducing extended cell protrusions and cell polarization, enhancing cell transmigration efficiency through confining spaces. We genetically edited human natural killer cell line (NK92) and mouse primary CD8 | [
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] | 2024-10-23 | 67 | 39441641 | [
"immune cells",
"immune cell infiltration",
"live cells",
"cell transmigration efficiency",
"cells",
"cell polarization",
"extended cell protrusions",
"intratumoral cancer cells",
"human natural killer cell line",
"Chimeric antigen receptor T cell therapies",
"solid tumors",
"solid tumor treatment",
"protein allosteric design",
"septin-7 function",
"Blue light",
"great success",
"LOV2",
"primary CD8",
"confining spaces",
"NK92",
"some liquid tumors",
"mouse",
"a light-controllable septin-7-LOV2 hybrid protein",
"a dense extracellular matrix",
"a blue light-responsive light-oxygen-voltage-sensing domain",
"the physical barrier",
"the preclinical results",
"septin-7 functions",
"the principal challenges",
"the tissue"
] | [
"cell transmigration",
"optogenetics",
"septin-7",
"tumor spheroid"
] | 0 | 10.1073/pnas.2405717121
10.1385/1592591175 | [
"Chen",
"Hnath",
"Sha",
"Beidler",
"Schell",
"Dokholyan"
] | [
"Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17033.",
"Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17033.\nDepartment of Biomedical Engineering, Pennsylvania State University, University Park, PA 16802.",
"Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17033.\nDepartment of Engineering Science and Mechanics, Pennsylvania State University, University Park, PA 16802.",
"Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, PA 17033.",
"Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, PA 17033.",
"Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17033.\nDepartment of Biomedical Engineering, Pennsylvania State University, University Park, PA 16802.\nDepartment of Biochemistry & Molecular Biology, Penn State College of Medicine, Hershey, PA 17033.\nDepartment of Chemistry, Pennsylvania State University, University Park, PA 16802."
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39441177 | 343 | Bispecific Antibodies as Bridging to BCMA CAR-T Cell Therapy for Relapsed/Refractory Multiple Myeloma. | Establishing a strategy for sequencing of T cell-redirecting therapies for relapsed/refractory multiple myeloma (RRMM) is a pressing clinical need. We longitudinally tracked the clinical and immunologic impact of bispecific T cell-engaging antibodies (BsAb) as bridging therapy (BT) to subsequent B-cell maturation antigen-directed chimeric antigen receptor T (CAR-T) cell therapies in 52 patients with RRMM. BsAbs were a potent and safe option for BT, achieving the highest overall response rate (100%) to BT compared with chemotherapy, anti-CD38, or anti-SLAMF7 antibody-based regimens (46%). We observed early CD4+CAR+ and delayed CD8+CAR+ T-cell expansion in patients receiving BsAbs as BT. In vitro cytotoxicity of CAR-T cells was comparable among BT options. Single-cell analyses revealed increased clonality in the CD4+ and CD8+ T-cell compartments in patients with previous exposure to BsAbs at leukapheresis and on day 30 after CAR-T cell infusion. This study demonstrates the feasibility and efficacy of BT with BsAbs for CAR-T cell therapy in RRMM. Significance: CAR-T cell therapy and BsAbs have revolutionized treatment of triple-class refractory multiple myeloma; however, optimal sequencing is unknown. We demonstrate that BT with BsAb before B-cell maturation antigen-directed CAR-T cell therapy is safe and effective, which might have implications for other hematologic malignancies as well. See related commentary by Bal and Costa, p. 10. | [
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] | 2024-10-23 | 46 | 39441177 | [
"CAR-T cell therapy",
"BT options",
"T cell-redirecting therapies",
"therapy",
"BT",
"bispecific T cell-engaging antibodies",
"CD8+ T-cell compartments",
"CD8+CAR+ T-cell expansion",
"CAR-T cell infusion",
"CAR-T cells",
"B-cell maturation antigen-directed CAR-T cell therapy",
"BsAbs",
"anti-SLAMF7",
"subsequent B-cell maturation antigen-directed chimeric antigen receptor",
"Single-cell analyses",
"related commentary",
"patients",
"other hematologic malignancies",
"triple-class refractory multiple myeloma",
"increased clonality",
"anti-SLAMF7 antibody-based regimens",
"RRMM",
"relapsed/refractory multiple myeloma",
"early CD4+CAR+",
"previous exposure",
"Bal",
"optimal sequencing",
"CAR-T",
"Costa",
"BsAb"
] | [] | 0 | 10.1158/2643-3230.BCD-24-0118 | [
"Fandrei",
"Seiffert",
"Rade",
"Rieprecht",
"Gagelmann",
"Born",
"Wiemers",
"Weidner",
"Kreuz",
"Schassberger",
"Koßmann",
"Mangold",
"Fürst",
"Fischer",
"Baber",
"Heyn",
"Wang",
"Bach",
"Hoffmann",
"Metzeler",
"Herling",
"Jentzsch",
"Franke",
"Köhl",
"Friedrich",
"Boldt",
"Reiche",
"Platzbecker",
"Vucinic",
"Merz"
] | [
"Department of Hematology, Hemostaseology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany.\nFraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany.",
"Department of Clinical Immunology, University Hospital Leipzig, Leipzig, Germany.",
"Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany.",
"Pharmacy, University Hospital Leipzig, Leipzig, Germany.",
"Department of Bone Marrow Transplantation, University Hospital Hamburg-Eppendorf UKE, Hamburg, Germany.",
"Department of Hematology, Hemostaseology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany.",
"Department of Hematology, Hemostaseology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany.",
"Bone Lab Dresden, Universitätsklinikum Carl Gustav Carus, TU Dresden, Dresden, Germany.",
"Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany.",
"Department of Clinical Immunology, University Hospital Leipzig, Leipzig, Germany.",
"Department of Clinical Immunology, University Hospital Leipzig, Leipzig, Germany.",
"Department of Clinical Immunology, University Hospital Leipzig, Leipzig, Germany.",
"Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service, Baden Wuerttemberg-Hessen, Ulm, University Hospital Ulm, Ulm, Germany.",
"Department of Hematology, Hemostaseology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany.",
"Institute of Laboratory Medicine, Clinical Chemistry, and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany.\nLeipzig Medical Biobank, Leipzig, Germany.",
"Department of Hematology, Hemostaseology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany.",
"Department of Hematology, Hemostaseology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany.",
"Department of Hematology, Hemostaseology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany.",
"Department of Hematology, Hemostaseology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany.",
"Department of Hematology, Hemostaseology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany.",
"Department of Hematology, Hemostaseology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany.",
"Department of Hematology, Hemostaseology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany.",
"Department of Hematology, Hemostaseology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany.",
"Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany.\nDepartment of Clinical Immunology, University Hospital Leipzig, Leipzig, Germany.",
"Department of Clinical Immunology, University Hospital Leipzig, Leipzig, Germany.",
"Department of Clinical Immunology, University Hospital Leipzig, Leipzig, Germany.",
"Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany.\nDepartment of Clinical Immunology, University Hospital Leipzig, Leipzig, Germany.\nCenter for Scalable Data Analytics and Artificial Intelligence (ScaDS.AI), Dresden, Germany.",
"Department of Hematology, Hemostaseology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany.",
"Department of Hematology, Hemostaseology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany.",
"Department of Hematology, Hemostaseology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany."
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] | [] | 5.484998 | 6.148286 |
39440883 | 344 | Toxicities and outcome after CD19-directed chimeric antigen receptor T-cell therapy for secondary neurolymphomatosis. | Lymphomatous infiltration of the peripheral nervous system (PNS), termed neurolymphomatosis, represents a distinct extranodal non-Hodgkin lymphoma variant with dismal outcome. CD19-directed chimeric antigen receptor (CD19-CAR) T-cell therapy has emerged as a safe and effective treatment for B-cell lymphomas. We aimed to assess toxicity and efficacy of CD19-CAR T-cells in neurolymphomatosis. Neurolymphomatosis patients treated with CD19 CAR T-cells were retrospectively identified at Massachusetts General Hospital over a six-year period. Toxicities were graded according to the ASTCT classification, management, and response rates were recorded. Eleven neurolymphomatosis patients were identified with a median of 2 lines of PNS-directed treatments (range: 1-3) prior to receiving CD19-CAR T-cells. Neurolymphomatosis localized to the nerve roots (8/11, 73%), plexus (5/11, 45%), peripheral (4/11, 36%) and cranial nerves (5/11, 45%). Low grade cytokine release syndrome (CRS) was detected in 8/11 (73%; grade 1: N = 7; grade 2: N = 1) cases. Low- and high-grade immune cell-associated neurotoxicity syndrome (ICANS) were recorded in 5/11 (45%; grade 1: N = 4; grade 2: N = 1) and 1/11 (9%; grade 4) patients, respectively. CRP levels at infusion were predictive of ICANS (area under the curve: 0.96, p = 0.01). Seven of eleven neurolymphomatosis patients (64%) responded to CD19-CAR T-cells. Complete remissions (CR) were achieved in three cases (27%), with 2 patients in sustained CR nine and 46 months after CD19-CAR infusion. Median progression-free survival (PFS) was 4 months. Collectively, CD19-CAR T-cell treatment was well tolerated and showed promising efficacy in recurrent neurolymphomatosis, a difficult to treat condition with unmet medical need. Findings suggest that CD19-CAR may sufficiently penetrate the blood-nerve barrier. Toxicity and outcomes were overall similar to CAR-T cell therapy in CNS lymphoma. | [
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] | 2024-10-23 | 1 | 39440883 | [
"Neurolymphomatosis patients",
"CD19 CAR T-cells",
"termed neurolymphomatosis",
"recurrent neurolymphomatosis",
"Low grade cytokine release syndrome",
"Neurolymphomatosis",
"neurolymphomatosis",
"CD19-CAR T-cell treatment",
"grade",
"CAR-T cell therapy",
"CD19-CAR T-cells",
"CD19-CAR",
"non-Hodgkin",
"promising efficacy",
"CD19-directed chimeric antigen receptor",
"Massachusetts General Hospital",
"CNS lymphoma",
"CD19-CAR infusion",
"sustained CR",
"B-cell lymphomas",
"cranial nerves",
"ICANS",
"high-grade immune cell-associated neurotoxicity syndrome",
"CD19-CAR) T-cell therapy",
"unmet medical need",
"PNS",
"Toxicities",
"Toxicity",
"toxicity",
"a distinct extranodal non-Hodgkin lymphoma"
] | [] | 0 | 10.1002/ajh.27505 | [
"Kaulen",
"Karschnia",
"Doubrovinskaia",
"Abramson",
"Martinez-Lage",
"Shankar",
"Choi",
"Barnes",
"El-Jawahri",
"Hochberg",
"Johnson",
"Soumerai",
"Wick",
"Maus",
"Chen",
"Frigault",
"Dietrich"
] | [
"Department of Neurology, Division of Neuro-Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.\nDepartment of Neurology, University Hospital Heidelberg, Heidelberg University, Heidelberg, Germany.\nClinical Cooperation Unit Neuro-Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.",
"Department of Neurology, Division of Neuro-Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.\nDepartment of Neurosurgery, Ludwig Maximilians University (LMU), Munich, Germany.\nDepartment of Neurosurgery, Friedrich-Alexander-University Erlangen/Nuernberg, Erlangen, Germany.",
"Department of Neurology, University Hospital Heidelberg, Heidelberg University, Heidelberg, Germany.\nClinical Cooperation Unit Neuro-Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.",
"Department of Medicine, Hematology, and Oncology Division, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.",
"Department of Pathology, Division of Neuropathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.",
"Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.",
"Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.",
"Department of Medicine, Hematology, and Oncology Division, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.",
"Department of Medicine, Hematology, and Oncology Division, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.",
"Department of Medicine, Hematology, and Oncology Division, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.",
"Department of Medicine, Hematology, and Oncology Division, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.",
"Department of Medicine, Hematology, and Oncology Division, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.",
"Department of Neurology, University Hospital Heidelberg, Heidelberg University, Heidelberg, Germany.\nClinical Cooperation Unit Neuro-Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.",
"Department of Medicine, Hematology, and Oncology Division, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.\nDepartment of Medicine, Cellular Immunotherapy Program, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.",
"Department of Medicine, Hematology, and Oncology Division, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.",
"Department of Medicine, Hematology, and Oncology Division, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.\nDepartment of Medicine, Cellular Immunotherapy Program, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.",
"Department of Neurology, Division of Neuro-Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA."
] | [
"39440883"
] | [] | 6.395251 | 4.959445 |
39439803 | 345 | Clinical advances and challenges associated with TCR-T cell therapy for cancer treatment. | T cell receptor (TCR)-T cell therapy is an innovative form of cancer immunotherapy that genetically modifies patients' T cells to target and destroy cancer cells. However, the current status of clinical trials of TCR-T cell therapy for the treatment of cancer remains unclear. This study aimed to comprehensively analyze the registration trials related to TCR-T cell therapy for the treatment of cancer.
A comprehensive search was conducted in the Trialtrove database for all clinical trials related to TCR-T cell therapy registered by August 1, 2024. Inclusion criteria focused on trials targeting TCR-T cell therapy for oncology, and excluded observational studies and incomplete data. Statistical analysis was performed on key trial characteristics, with between-group comparisons utilizing chi-square or Fisher's exact tests.
Analysis of 174 eligible clinical trials revealed that TCR-T cell therapy exhibits significant efficacy across various tumor types, particularly in refractory hematologic malignancies and certain solid tumors. Additionally, combining TCR-T cell therapy with other immunotherapies enhanced these anti-tumor effects.
TCR-T cell therapy holds substantial promise for cancer treatment. Future research should focus on optimizing treatment protocols, enhancing efficacy, and minimizing prices to fully realize the potential of this therapy. | [
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10.1016/j.ccell.2020.05.013 | [
"Li",
"Zhang",
"Fu",
"Xing",
"Cai",
"Li",
"Xu",
"Tong"
] | [
"Heilongjiang University of Chinese Medicine, Harbin, China.",
"School of Mechanical and Electrical Engineering, Harbin Institute of Technology, Harbin, China.",
"Brandeis University, Waltham, MA, United States.",
"First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China.",
"First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China.",
"Heilongjiang University of Chinese Medicine, Harbin, China.",
"Heilongjiang University of Chinese Medicine, Harbin, China.",
"First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China."
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39439295 | 346 | Evolving strategies to overcome barriers in CAR-T cell therapy for acute myeloid leukemia. | Acute myeloid leukemia (AML) is a complex and heterogeneous disease characterized by an aggressive clinical course and limited efficacious treatment options in the relapsed/refractory (R/R) setting. Chimeric antigen receptor (CAR)-modified T (CAR-T) cell immunotherapy is an investigational treatment strategy for R/R AML that has shown some promise. However, obstacles to successful CAR-T cell immunotherapy for AML remain.
In analyses of clinical trials of CAR-T cell therapy for R/R AML, complete responses without measurable residual disease have been reported, but the durability of those responses remains unclear. Significant barriers to successful CAR-T cell therapy in AML include the scarcity of suitable tumor-target antigens (TTA), inherent T cell functional deficits, and the immunoinhibitory and hostile tumor microenvironment (TME). This review will focus on these barriers to successful CAR-T cell therapy in AML, and discuss scientific advancements and evolving strategies to overcome them.
Achieving durable remissions in R/R AML will likely require a multifaceted approach that integrates advancements in TTA selection, enhancement of the intrinsic quality of CAR-T cells, and development of strategies to overcome inhibitory mechanisms in the AML TME. | [
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] | 2024-10-23 | 1 | 39439295 | [
"inherent T cell functional deficits",
"AML",
"successful CAR-T cell therapy",
"successful CAR-T cell immunotherapy",
"R/R AML",
"CAR-T cell therapy",
"CAR-T cells",
"measurable residual disease",
"efficacious treatment options",
"evolving strategies",
"TTA selection",
"complete responses",
"scientific advancements",
"Chimeric antigen receptor",
"strategies",
"clinical trials",
"Acute myeloid leukemia",
"advancements",
"TTA",
"the AML TME",
"Significant barriers",
"inhibitory mechanisms",
"durable remissions",
"suitable tumor-target antigens",
"an investigational treatment strategy",
"(AML",
"TME",
"an aggressive clinical course",
"enhancement",
"CAR-T"
] | [
"AML",
"CAR-T cells",
"T cell fitness",
"acute myeloid leukemia",
"chimeric antigen receptor",
"immunotherapy",
"tumor antigen",
"tumor microenvironment"
] | 0 | 10.1080/17474086.2024.2420614 | [
"Colonne",
"Kimble",
"Turtle"
] | [
"Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.",
"Translational Science and Therapeutic Division, Fred Hutchinson Cancer Center, Seattle, USA.\nDepartment of Medicine, Division of Hematology and Oncology, University of Washington, Seattle, USA.",
"Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.\nHaematology and Transfusion Medicine, Royal North Shore Hospital, Sydney, Australia."
] | [
"39439295"
] | [] | 6.827045 | 7.211897 |
39438476 | 347 | MEK inhibition prevents CAR-T cell exhaustion and differentiation via downregulation of c-Fos and JunB. | Clinical evidence supports the notion that T cell exhaustion and terminal differentiation pose challenges to the persistence and effectiveness of chimeric antigen receptor-T (CAR-T) cells. MEK1/2 inhibitors (MEKIs), widely used in cancer treatment due to their ability to inhibit aberrant MAPK signaling, have shown potential synergistic effects when combined with immunotherapy. However, the impact and mechanisms of MEKIs on CAR-T cells remain uncertain and controversial. To address this, we conducted a comprehensive investigation to determine whether MEKIs enhance or impair the efficacy of CAR-T cells. Our findings revealed that MEKIs attenuated CAR-T cell exhaustion and terminal differentiation induced by tonic signaling and antigen stimulation, thereby improving CAR-T cell efficacy against hematological and solid tumors. Remarkably, these effects were independent of the specific scFvs and costimulatory domains utilized in CARs. Mechanistically, analysis of bulk and single-cell transcriptional profiles demonstrates that the effect of MEK inhibition was related to diminish anabolic metabolism and downregulation of c-Fos and JunB. Additionally, the overexpression of c-Fos or JunB in CAR-T cells counteracted the effects of MEK inhibition. Furthermore, our Cut-and-Tag assay revealed that MEK inhibition downregulated the JunB-driven gene profiles associated with exhaustion, differentiation, anergy, glycolysis, and apoptosis. In summary, our research unveil the critical role of the MAPK-c-Fos-JunB axis in driving CAR-T cell exhaustion and terminal differentiation. These mechanistic insights significantly broaden the potential application of MEKIs to enhance the effectiveness of CAR-T therapy. | [
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"T cell exhaustion",
"CAR-T cell exhaustion",
"potential synergistic effects",
"terminal differentiation",
"CAR-T cell efficacy",
"MEKIs",
"CAR-T cells",
"MEK inhibition",
"CARs",
"exhaustion",
"differentiation",
"CAR-T therapy",
"cancer treatment",
"anabolic metabolism",
"effectiveness",
"JunB",
"bulk and single-cell transcriptional profiles",
"MEK1/2 inhibitors",
"Clinical evidence",
"CAR-T",
"downregulation",
"tonic",
"JunB.",
"challenges",
"c-Fos",
"the JunB-driven gene profiles",
"anergy",
"inhibitors",
"the potential application",
"summary"
] | [] | 0 | 10.1038/s41392-024-01986-y | [
"Wang",
"Tao",
"Chen",
"Jiang",
"Li",
"Chang",
"Wei",
"Lai",
"Zhang",
"Pan",
"Ding",
"Liang",
"Cui",
"Shao",
"Teng",
"Gu",
"Wei",
"Kong",
"Si",
"Han",
"Fu",
"Lin",
"Yu",
"Li",
"Wang",
"Hu",
"Qian",
"Huang"
] | [
"Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.\nLiangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.\nInstitute of Hematology, Zhejiang University, Hangzhou, 310003, China.\nZhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, 310003, China.",
"Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.\nLiangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.\nInstitute of Hematology, Zhejiang University, Hangzhou, 310003, China.\nZhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, 310003, China.",
"Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.\nLiangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.\nInstitute of Hematology, Zhejiang University, Hangzhou, 310003, China.\nZhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, 310003, China.",
"Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.\nInstitute of Hematology, Zhejiang University, Hangzhou, 310003, China.\nZhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, 310003, China.\nCenter of Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China.",
"Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.\nLiangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.\nInstitute of Hematology, Zhejiang University, Hangzhou, 310003, China.\nZhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, 310003, China.",
"Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.\nLiangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.\nInstitute of Hematology, Zhejiang University, Hangzhou, 310003, China.\nZhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, 310003, China.",
"Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.\nLiangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.\nInstitute of Hematology, Zhejiang University, Hangzhou, 310003, China.\nZhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, 310003, China.",
"Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.\nLiangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.\nInstitute of Hematology, Zhejiang University, Hangzhou, 310003, China.\nZhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, 310003, China.",
"Department of Hematology, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325200, China.",
"Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.\nLiangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.\nInstitute of Hematology, Zhejiang University, Hangzhou, 310003, China.\nZhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, 310003, China.",
"Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.\nLiangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.\nInstitute of Hematology, Zhejiang University, Hangzhou, 310003, China.\nZhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, 310003, China.",
"Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.\nLiangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.\nInstitute of Hematology, Zhejiang University, Hangzhou, 310003, China.\nZhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, 310003, China.",
"Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.\nLiangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.\nInstitute of Hematology, Zhejiang University, Hangzhou, 310003, China.\nZhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, 310003, China.",
"Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.\nLiangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.\nInstitute of Hematology, Zhejiang University, Hangzhou, 310003, China.\nZhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, 310003, China.",
"Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.\nLiangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.\nInstitute of Hematology, Zhejiang University, Hangzhou, 310003, China.\nZhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, 310003, China.",
"Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.\nLiangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.\nInstitute of Hematology, Zhejiang University, Hangzhou, 310003, China.\nZhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, 310003, China.",
"Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.\nLiangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.\nInstitute of Hematology, Zhejiang University, Hangzhou, 310003, China.\nZhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, 310003, China.",
"Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.\nLiangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.\nInstitute of Hematology, Zhejiang University, Hangzhou, 310003, China.\nZhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, 310003, China.",
"Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.\nLiangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.\nInstitute of Hematology, Zhejiang University, Hangzhou, 310003, China.\nZhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, 310003, China.",
"Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.\nLiangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.\nInstitute of Hematology, Zhejiang University, Hangzhou, 310003, China.\nZhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, 310003, China.",
"Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.\nLiangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.\nInstitute of Hematology, Zhejiang University, Hangzhou, 310003, China.\nZhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, 310003, China.",
"Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.\nLiangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.\nInstitute of Hematology, Zhejiang University, Hangzhou, 310003, China.\nZhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, 310003, China.",
"Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.\nLiangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.\nInstitute of Hematology, Zhejiang University, Hangzhou, 310003, China.\nZhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, 310003, China.",
"Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.\nLiangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.\nInstitute of Hematology, Zhejiang University, Hangzhou, 310003, China.\nZhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, 310003, China.",
"Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.\nLiangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.\nInstitute of Hematology, Zhejiang University, Hangzhou, 310003, China.\nZhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, 310003, China.",
"Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.\nLiangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China.\nInstitute of Hematology, Zhejiang University, Hangzhou, 310003, China.\nZhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, 310003, China.",
"Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China. [email protected].\nInstitute of Hematology, Zhejiang University, Hangzhou, 310003, China. [email protected].\nZhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, 310003, China. [email protected].\nCenter of Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China. [email protected].",
"Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China. [email protected].\nLiangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, China. [email protected].\nInstitute of Hematology, Zhejiang University, Hangzhou, 310003, China. [email protected].\nZhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, 310003, China. [email protected]."
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39437676 | 348 | Challenges and future perspectives for high-throughput chimeric antigen receptor T cell discovery. | Novel chimeric antigen receptor (CAR) T cell designs are being developed to overcome challenges with tumor recognition, trafficking, on-target but off-tumor binding, cytotoxicity, persistence, and immune suppression within the tumor microenvironment. Whereas traditional CAR engineering is an iterative, hypothesis-driven process in which novel designs are rationally constructed and tested for in vivo efficacy, drawing from the fields of small-molecule and protein-based therapeutic discovery, we consider how high-throughput, functional screening technologies are beginning to be applied for the development of promising CAR candidates. We review how the development of high-throughput screening methods has the potential to streamline the CAR discovery process, ultimately improving efficiency and clinical efficacy. | [
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] | 2024-10-23 | 83 | 39437676 | [
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] | [] | 0 | 10.1016/j.copbio.2024.103216 | [
"Butler",
"Ackerman"
] | [
"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.",
"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA; Thayer School of Engineering, Dartmouth College, Hanover, NH, USA. Electronic address: [email protected]."
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] | [] | 8.710443 | 4.441675 |
39433885 | 349 | From TCR fundamental research to innovative chimeric antigen receptor design. | Engineered T cells that express chimeric antigen receptors (CARs) have transformed the treatment of haematological cancers. CARs combine the tumour-antigen-binding function of antibodies with the signalling functions of the T cell receptor (TCR) ζ chain and co-stimulatory receptors. The resulting constructs aim to mimic the TCR-based and co-receptor-based activation of T cells. Although these have been successful for some types of cancer, new CAR formats are needed, to limit side effects and broaden their use to solid cancers. Insights into the mechanisms of TCR signalling, including the identification of signalling motifs that are not present in the TCR ζ chain and mechanistic insights in TCR activation, have enabled the development of CAR formats that outcompete the current CARs in preclinical mouse models and clinical trials. In this Perspective, we explore the mechanistic rationale behind new CAR designs. | [
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10.1073/pnas.1703559114 | [
"Minguet",
"Maus",
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] | [
"Signalling Research Centers BIOSS and CIBSS, Freiburg, Germany. [email protected].\nDepartment of Synthetic Immunology, Faculty of Biology, University of Freiburg, Freiburg, Germany. [email protected].\nCentre for Chronic Immunodeficiency (CCI), Faculty of Medicine, University of Freiburg, Freiburg, Germany. [email protected].",
"Cellular Immunotherapy Program and Krantz Family Center for Cancer Research, Mass General Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.",
"Signalling Research Centers BIOSS and CIBSS, Freiburg, Germany. [email protected].\nCentre for Chronic Immunodeficiency (CCI), Faculty of Medicine, University of Freiburg, Freiburg, Germany. [email protected].\nDepartment of Immunology, Faculty of Biology, University of Freiburg, Freiburg, Germany. [email protected]."
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] | [] | 8.537309 | 4.772032 |
39433427 | 350 | Microenvironmental alkalization promotes the therapeutic effects of MSLN-CAR-T cells. | Triple-negative breast cancer (TNBC) is characterized by high invasion, prone metastasis, frequent recurrence and poor prognosis. Unfortunately, the curative effects of current clinical therapies, including surgery, radiotherapy, chemotherapy and immunotherapy, are still limited in patients with TNBC. In this study, we showed that the heterogeneous expression at the protein level and subcellular location of mesothelin (MSLN), a potential target for chimeric antigen receptor-T (CAR-T) cell therapy in TNBC, which is caused by acidification of the tumor microenvironment, may be the main obstacle to therapeutic efficacy. Alkalization culture or sodium bicarbonate administration significantly promoted the membrane expression of MSLN and enhanced the killing efficiency of MSLN-CAR-T cells both | [
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10.2147/IJN.S257741 | [
"Wu",
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"Zhai",
"Liu",
"Wang",
"Li",
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] | [
"Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, Chongqing, China.\nJin-feng Laboratory, Chongqing, Chongqing, China.",
"Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, Chongqing, China.",
"Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, Chongqing, China.\nDeaprtment of Oncology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, Chongqing, China.",
"Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, Chongqing, China.",
"Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, Chongqing, China.",
"Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, Chongqing, China.",
"Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, Chongqing, China.\nJin-feng Laboratory, Chongqing, Chongqing, China.",
"Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, Chongqing, China.\nJin-feng Laboratory, Chongqing, Chongqing, China.",
"International Joint Research Center for Precision Biotherapy, Ministry of Science and Technology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, Chongqing, China.",
"Deaprtment of Oncology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, Chongqing, China [email protected] [email protected].",
"Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, Chongqing, China [email protected] [email protected].\nJin-feng Laboratory, Chongqing, Chongqing, China."
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] | 2024-10-21 | 59 | 39431011 | [] | [
"CAR-T",
"CD39",
"Nanobody",
"Ovarian cancer",
"Tumor microenvironment"
] | 0 | 10.7150/thno.97590 | [
"Zhang",
"Li",
"Deng",
"Ge",
"Yi",
"Wang",
"Wang",
"Zhou",
"Kong",
"Liu",
"Zhang",
"Li",
"He",
"Zhu"
] | [
"Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China.\nR&D Department, OriCell Therapeutics Co. Ltd., 1227 Zhangheng Road, Shanghai, 201203, China.",
"R&D Department, OriCell Therapeutics Co. Ltd., 1227 Zhangheng Road, Shanghai, 201203, China.",
"R&D Department, OriCell Therapeutics Co. Ltd., 1227 Zhangheng Road, Shanghai, 201203, China.",
"Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China.\nR&D Department, OriCell Therapeutics Co. Ltd., 1227 Zhangheng Road, Shanghai, 201203, China.",
"R&D Department, OriCell Therapeutics Co. Ltd., 1227 Zhangheng Road, Shanghai, 201203, China.",
"R&D Department, OriCell Therapeutics Co. Ltd., 1227 Zhangheng Road, Shanghai, 201203, China.",
"R&D Department, OriCell Therapeutics Co. Ltd., 1227 Zhangheng Road, Shanghai, 201203, China.",
"R&D Department, OriCell Therapeutics Co. Ltd., 1227 Zhangheng Road, Shanghai, 201203, China.",
"Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China.",
"R&D Department, OriCell Therapeutics Co. Ltd., 1227 Zhangheng Road, Shanghai, 201203, China.",
"R&D Department, OriCell Therapeutics Co. Ltd., 1227 Zhangheng Road, Shanghai, 201203, China.",
"R&D Department, OriCell Therapeutics Co. Ltd., 1227 Zhangheng Road, Shanghai, 201203, China.",
"R&D Department, OriCell Therapeutics Co. Ltd., 1227 Zhangheng Road, Shanghai, 201203, China.",
"Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China.\nDepartment of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.\nDepartment of Obstetrics and Gynecology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325015, China."
] | [
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|
39430751 | 352 | A structural, genetic and clinical comparison of CAR-T cells and CAR-NK cells: companions or competitors? | In recent years, following the groundbreaking achievements of chimeric antigen receptor (CAR) T cell therapy in hematological cancers, and advancements in cell engineering technologies, the exploration of other immune cells has garnered significant attention. CAR-Therapy extended beyond T cells to include CAR natural killer (NK) cells and CAR-macrophages, which are firmly established in the clinical trial landscape. Less conventional immune cells are also making their way into the scene, such as CAR mucosal-associated invariant T (MAIT) cells. This progress is advancing precision medicine and facilitating the development of ready-to-use biological treatments. However, in view of the unique features of natural killer cells, adoptive NK cell immunotherapy has emerged as a universal, allogenic, "off-the shelf" therapeutic strategy. CAR-NK cytotoxic cells present targeted tumor specificity but seem to be devoid of the side effects associated with CAR-T cells. CAR-NK cells appear to be potentially promising candidates for cancer immunotherapy. However, their application is hindered by significant challenges, particularly the limited persistence of CAR-NK cells in the body, which poses a hurdle to their sustained effectiveness in treating cancer. Based upon the foregoing, this review discusses the current status and applications of both CAR-T cells and CAR-NK cells in hematological cancers, and provides a comparative analysis of the structure, genetics, and clinical outcomes between these two types of genetically modified immune cells. | [
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10.1038/s41591-021-01621-1 | [
"Andrea",
"Chiron",
"Sarrabayrouse",
"Bessoles",
"Hacein-Bey-Abina"
] | [
"Department of Biology, Faculty of Arts and Sciences, Saint George University of Beirut, Beirut, Lebanon.",
"Université Paris Cité, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Unité des Technologies Chimiques et Biologiques pour la Santé (UTCBS), Paris, France.\nClinical Immunology Laboratory, Groupe Hospitalier Universitaire Paris Saclay, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Le-Kremlin-Bicêtre, France.",
"Université Paris Cité, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Unité des Technologies Chimiques et Biologiques pour la Santé (UTCBS), Paris, France.",
"Université Paris Cité, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Unité des Technologies Chimiques et Biologiques pour la Santé (UTCBS), Paris, France.",
"Université Paris Cité, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Unité des Technologies Chimiques et Biologiques pour la Santé (UTCBS), Paris, France.\nClinical Immunology Laboratory, Groupe Hospitalier Universitaire Paris Saclay, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Le-Kremlin-Bicêtre, France."
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39428507 | 353 | MOG-specific CAR Tregs: a novel approach to treat multiple sclerosis. | Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system (CNS) with the immune system attacking myelin sheaths leading to neuronal death. While several disease-modifying therapies are available to treat MS, these therapies are not universally effective and do not stop disease progression. More personalized long-term treatment options that target specific aspects of the disease, such as reducing relapse frequency, delaying disability accumulation, and addressing symptoms that impact daily functioning, as well as therapies that can promote neuroprotection and repair are needed. Chimeric Antigen Receptor (CAR) Tcell therapies have revolutionized cancer treatment by intravenously (IV) administering a defined dose of T cells with high specificity provided by the CAR. An autologous CAR T cell therapy using suppressive regulatory T cells (Tregs) inducing long-lasting tolerance would be the ideal treatment for patients. Hence, we expanded the application of CAR-T cells by introducing a CAR into Tregs to treat MS patients. We developed a myelin oligodendrocyte glycoprotein (MOG)-specific CAR Treg cell therapy for patients with MS. MOG is expressed on the outer membrane of the myelin sheath, the insulating layer the forms around nerves, making it an ideal target for CAR Treg therapy. Our lead candidate is a 2nd generation CAR, composed of an anti-MOG scFv screened from a large human library. In vitro, we demonstrated CAR-dependent functionality and showed efficacy in vivo using a passive EAE mouse model. Additionally, the MOG-CAR Tregs have very low tonic signaling with a desirable signal-to-noise ratio resulting in a highly potent CAR. In summary our data suggest that MOG-CAR Tregs are a promising MS treatment option with the potential to induce long-lasting tolerance in patients. | [
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] | [
"CAR-Treg",
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] | 0 | 10.1186/s12974-024-03262-w | [
"Frikeche",
"David",
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"Treguer",
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"Rouquier",
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] | [
"Research, Sangamo Therapeutics, Allée de la Nertière, Valbonne, 06560, France.",
"Research, Sangamo Therapeutics, Allée de la Nertière, Valbonne, 06560, France.",
"Research, Sangamo Therapeutics, Allée de la Nertière, Valbonne, 06560, France.",
"Research, Sangamo Therapeutics, Allée de la Nertière, Valbonne, 06560, France.",
"Research, Sangamo Therapeutics, Allée de la Nertière, Valbonne, 06560, France.",
"Research, Sangamo Therapeutics, Allée de la Nertière, Valbonne, 06560, France.",
"Research, Sangamo Therapeutics, Allée de la Nertière, Valbonne, 06560, France.",
"Research, Sangamo Therapeutics, Allée de la Nertière, Valbonne, 06560, France.",
"Research, Sangamo Therapeutics, Allée de la Nertière, Valbonne, 06560, France.",
"Research, Sangamo Therapeutics, Allée de la Nertière, Valbonne, 06560, France.",
"Research, Sangamo Therapeutics, Allée de la Nertière, Valbonne, 06560, France.",
"Research, Sangamo Therapeutics, Allée de la Nertière, Valbonne, 06560, France.",
"Research, Sangamo Therapeutics, Allée de la Nertière, Valbonne, 06560, France.",
"Research, Sangamo Therapeutics, Allée de la Nertière, Valbonne, 06560, France.",
"Research, Sangamo Therapeutics, Allée de la Nertière, Valbonne, 06560, France.",
"Research, Sangamo Therapeutics, Allée de la Nertière, Valbonne, 06560, France.",
"Research, Sangamo Therapeutics, Allée de la Nertière, Valbonne, 06560, France. [email protected]."
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39426936 | 354 | Cellular and immunotherapies for myelodysplastic syndromes. | In this review article, we outline the current landscape of immune and cell therapy-based approaches for patients with myelodysplastic syndromes (MDS). Given the well characterized graft-versus-leukemia (GVL) effect observed with allogeneic hematopoietic cell transplantation, and the known immune escape mechanisms observed in MDS cells, significant interest exists in developing immune-based approaches to treat MDS. These attempts have included antibody-based drugs that block immune escape molecules, such as inhibitors of the PD-1/PD-L1 and TIM-3/galectin-9 axes that mediate interactions between MDS cells and T-lymphocytes, as well as antibodies that block the CD47/SIRPα interaction, which mediates macrophage phagocytosis. Unfortunately, these approaches have been largely unsuccessful. There is significant potential for T-cell engaging therapies and chimeric antigen receptor T (CAR-T) cells, but there are also several limitations to these approaches that are unique to MDS. However, many of these limitations may be overcome by the next generation of cellular therapies, including those with engineered T-cell receptors or natural killer (NK)-cell based platforms. Regardless of the approach, all these immune cells are subject to the complex bone marrow microenvironment in MDS, which harbours a variable and heterogeneous mix of pro-inflammatory cytokines and immunosuppressive elements. Understanding this interaction will be paramount to ensuring the success of immune and cellular therapies in MDS. | [
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] | 2024-10-20 | 1 | 39426936 | [
"MDS cells",
"allogeneic hematopoietic cell transplantation",
"immune escape molecules",
"MDS",
"cellular therapies",
"pro-inflammatory cytokines",
"engineered T-cell receptors",
"immune and cell therapy-based approaches",
"interactions",
"several limitations",
"immune and cellular therapies",
"significant interest",
"developing immune-based approaches",
"significant potential",
"the known immune escape mechanisms",
"T-cell engaging therapies and chimeric antigen receptor T (CAR-T) cells",
"natural killer (NK)-cell based platforms",
"immunosuppressive elements",
"myelodysplastic syndromes",
"antibody-based drugs",
"macrophage phagocytosis",
"leukemia",
"all these immune cells",
"PD-1",
"inhibitors",
"the complex bone marrow microenvironment",
"patients",
"T-lymphocytes",
"the CD47/SIRPα interaction",
"the approach"
] | [
"CAR-T cells",
"Immunotherapy",
"Inflammation",
"Microenvironment",
"Myelodysplastic syndrome"
] | 0 | 10.1053/j.seminhematol.2024.09.006 | [
"Stubbins",
"Cherniawsky",
"Karsan"
] | [
"Leukemia/BMT Program of BC, BC Cancer, Vancouver V5Z 1M9, BC, Canada; Division of Hematology, Department of Medicine, University of British Columbia, Vancouver V5Z 1M9, BC, Canada. Electronic address: [email protected].",
"Leukemia/BMT Program of BC, BC Cancer, Vancouver V5Z 1M9, BC, Canada; Division of Hematology, Department of Medicine, University of British Columbia, Vancouver V5Z 1M9, BC, Canada.",
"Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC V5Z 1L3, Canada. Electronic address: [email protected]."
] | [
"39426936"
] | [] | 6.303279 | 7.063177 |
39425546 | 355 | Nanotechnology-Assisted CAR-T-Cell Therapy for Tumor Treatment. | The adoptive transfer of T cells redirected by chimeric antigen receptors (CARs) has made a dramatic breakthrough in defeating hematological malignancies. However, in solid tumor treatment, CAR-T-cell therapy has attained limited therapeutic benefits due to insufficient infiltration and expansion, rapidly diminishing function following adoptive transfer, and severe life-threatening toxicities. To address these challenges, advancements in nanotechnology have utilized innovative approaches to devise stronger CAR-T cells with reduced toxicity and enhanced anti-tumor activity. Equipping CAR-T cells with multifunctional nanoparticles can abrogate immunosuppressive signaling in the tumor area, augment the functions of CAR-T cells, and mitigate their toxicity against normal tissues. Additionally, nanoparticle-mediated CAR-T-cell programming has the potential to optimize manufacturing and lower the cost for the broader implementation of CAR-T-cell therapy. In this review, we introduce the obstacles to be surmounted in CAR-T-cell therapy, highlight the nanotechnology-based strategies that aim to enrich the therapeutic applications of CAR-T-cell therapy, and envision the prospect of nanoparticle-assisted CAR-T-cell therapy. | [
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] | 2024-10-19 | 1 | 39425546 | [
"T cells",
"stronger CAR-T cells",
"CAR-T cells",
"CARs",
"reduced toxicity",
"CAR-T-cell therapy",
"limited therapeutic benefits",
"enhanced anti-tumor activity",
"adoptive transfer",
"multifunctional nanoparticles",
"nanoparticle-assisted CAR-T-cell therapy",
"chimeric antigen receptors",
"solid tumor treatment",
"nanoparticle-mediated CAR-T-cell programming",
"nanotechnology",
"innovative approaches",
"insufficient infiltration",
"function",
"immunosuppressive signaling",
"hematological malignancies",
"normal tissues",
"manufacturing",
"expansion",
"advancements",
"The adoptive transfer",
"the therapeutic applications",
"the tumor area",
"a dramatic breakthrough",
"the nanotechnology-based strategies",
"the broader implementation"
] | [] | 0 | 10.1002/wnan.2005 | [
"Wang",
"Barrett",
"Hu"
] | [
"Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin, USA.\nCarbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.\nWisconsin Center for NanoBioSystems, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin, USA.",
"Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin, USA.",
"Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin, USA.\nCarbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.\nWisconsin Center for NanoBioSystems, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin, USA."
] | [
"39425546"
] | [] | 9.955402 | 3.591237 |
39425222 | 356 | Antibody-targeted T cells and natural killer cells for cancer immunotherapy. | Adoptive cell cancer therapies aim to re-engineer a patient's immune cells to mount an anti-cancer response. Chimeric antigen receptor T and natural killer cells have been engineered and proved successful in treating some cancers; however, the genetic methods for engineering are laborious, expensive, and inefficient and can cause severe toxicities when they over-proliferate.
We examined whether the cell-killing capacity of activated T and NK cells could be targeted to cancer cells by anchoring antibodies to their cell surface. Using metabolic glycoengineering to introduce azide moieties to the cellular surface, we covalently attached a dibenzocyclooctyne-modified antibody using the strain-promoted alkyne azide cycloaddition reaction, creating antibody-conjugated T and NK cells. We targeted the immune cells to tumors possessing the xenoantigen, N-glycolyl neuraminic acid GM3 ganglioside, using the 14F7hT antibody. These activated T and NK cells are "armed" with tumour-homing capabilities that specifically lyses antigen-positive cancer cells without off-target toxicities. Moreover, when exposed to target cells, 14F7hT-conjugated T cells that are not preactivated exhibit increased perforin, granzyme, CD69, and CD25 expression and specific cell killing.
This research shows the potential for a non-genetic method for redirecting cytotoxic immune cells as a feasible and effective approach for tumor-targeted cell immunotherapy. | [
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] | [] | 0 | 10.1186/s12951-024-02898-3 | [
"Sutherland",
"Parlekar",
"Livingstone",
"Medina",
"Bernhard",
"García",
"DeCoteau",
"Geyer"
] | [
"Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada.",
"Department of Health Sciences, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada.",
"Department of Health Sciences, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada.",
"Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada.",
"Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada.",
"Center for Molecular Immunology, 11600, Havana, Cuba.",
"Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada.",
"Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada. [email protected]."
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39423821 | 357 | Targeting HLA-E-overexpressing cancers with a NKG2A/C switch receptor. | Human leukocyte antigen (HLA)-E is overexpressed by a large proportion of solid tumors, including malignant glioblastoma, and acts as a major checkpoint for NKG2A
We engineered a chimeric A/C switch receptor, combining the high HLA-E binding affinity of the NKG2A receptor ectodomain with the activating signaling of the NKG2C receptor endodomain. The cytotoxic function of A/C switch-transduced NK and T cells was evaluated against tumor cells with varying levels of HLA-E expression. In vivo efficacy was assessed using a xenograft model of glioblastoma.
A/C switch-transduced NK and T cells exhibited superior and specific cytotoxicity against tumor cells with medium to high HLA-E expression. A/C switch-expressing human T cells demonstrated enhanced anti-tumor function in a glioblastoma xenograft model. The activity of the modified T cells was governed by an equilibrium between A/C switch levels and HLA-E expression, creating a therapeutic window to minimize on-target, off-tumor toxicities. Normal cells remained insensitive to A/C switch T cells, even after interferon (IFN)-γ pretreatment to induce HLA-E expression.
The A/C switch receptor effectively targets tumor cells expressing high levels of HLA-E, either alone or in combination with other engineered specificities, to overcome the suppressive NKG2A/HLA-E checkpoint. This approach offers a promising therapeutic strategy with a favorable safety profile for targeting HLA-E-overexpressing tumors.
This work was funded by The Research Council of Norway, the Norwegian Cancer Society, and the National Cancer Institute. | [
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] | 2024-10-19 | 1 | 39423821 | [
"tumor cells",
"Normal cells",
"solid tumors",
"high levels",
"A/C switch levels",
"high HLA-E expression",
"enhanced anti-tumor function",
"HLA-E-overexpressing tumors",
"A/C switch T cells",
"HLA-E expression",
"other engineered specificities",
"malignant glioblastoma",
"varying levels",
"Human leukocyte antigen",
"a chimeric A/C switch receptor",
"HLA-E",
"The A/C switch receptor",
"A/C switch-expressing human T cells",
"the high HLA-E binding affinity",
"glioblastoma",
"A/C switch-transduced NK and T cells",
"NKG2A",
"Norway",
"vivo efficacy",
"the suppressive NKG2A/HLA-E checkpoint",
"the Norwegian Cancer Society",
"a glioblastoma xenograft model",
"HLA)-E",
"the modified T cells",
"a promising therapeutic strategy"
] | [
"CAR T cells",
"HLA-E",
"NK cells",
"NKG2 receptor family",
"Pre-clinical research",
"cancer immunotherapy",
"glioblastoma"
] | 0 | 10.1016/j.medj.2024.09.010 | [
"Sætersmoen",
"Kotchetkov",
"Torralba-Raga",
"Mansilla-Soto",
"Sohlberg",
"Krokeide",
"Hammer",
"Sadelain",
"Malmberg"
] | [
"Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.",
"Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Center for Cell Engineering and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.",
"Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.",
"Center for Cell Engineering and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.",
"Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.",
"Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.",
"Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.",
"Center for Cell Engineering and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.",
"Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. Electronic address: [email protected]."
] | [
"39423821"
] | [] | 10.403936 | 6.716634 |
39421021 | 358 | CAR-macrophage: Breaking new ground in cellular immunotherapy. | Chimeric Antigen Receptor (CAR) technology has revolutionized cellular immunotherapy, particularly with the success of CAR-T cells in treating hematologic malignancies. However, CAR-T cells have the limited efficacy of against solid tumors. To address these limitations, CAR-macrophages (CAR-Ms) leverage the innate properties of macrophages with the specificity and potency of CAR technology, offering a novel and promising approach to cancer immunotherapy. Preclinical studies have shown that CAR-Ms can effectively target and destroy tumor cells, even within challenging microenvironments, by exhibiting direct cytotoxicity and enhancing the recruitment and activation of other immune cells. Additionally, the favorable safety profile of macrophages and their persistence within solid tumors position CAR-Ms as potentially safer and more durable therapeutic options compared to CAR-T cells. This review explores recent advancements in CAR-Ms technology, including engineering strategies to optimize their anti-tumor efficacy and preclinical evidence supporting their use. We also discuss the challenges and future directions in developing CAR-Ms therapies, emphasizing their potential to revolutionize cellular immunotherapy. By harnessing the unique properties of macrophages, CAR-Ms offer a groundbreaking approach to overcoming the current limitations of CAR-T cell therapies, paving the way for more effective and sustainable cancer treatments. | [
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"macrophages",
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"cancer immunotherapy",
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"activation",
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10.1016/j.tibtech.2024.01.006 | [
"Huang",
"Bei",
"Hu",
"Li"
] | [
"Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China.\nSchool of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.",
"Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China.\nSchool of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.",
"Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China.",
"Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China.\nSchool of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.\nShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.\nUniversity of Chinese Academy of Sciences, Beijing, China."
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39420062 | 359 | Targeting overexpressed antigens in glioblastoma via CAR T cells with computationally designed high-affinity protein binders. | Chimeric antigen receptor (CAR) T cells targeting receptors on tumour cells have had limited success in patients with glioblastoma. Here we report the development and therapeutic performance of CAR constructs leveraging protein binders computationally designed de novo to have high affinity for the epidermal growth factor receptor (EGFR) or the tumour-associated antigen CD276, which are overexpressed in glioblastoma. With respect to T cells with a CAR using an antibody-derived single-chain variable fragment as antigen-binding domain, the designed binders on CAR T cells promoted the proliferation of the cells, the secretion of cytotoxic cytokines and their resistance to cell exhaustion, and improved antitumour performance in vitro and in vivo. Moreover, CARs with the binders exhibited higher surface expression and greater resistance to degradation, as indicated by bulk and single-cell transcriptional profiling of the cells. The de novo design of binding domains for specific tumour antigens may potentiate the antitumour efficacy of CAR T cell therapies for other solid cancers. | [
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10.1186/1471-2105-14-7 | [
"Xia",
"Jin",
"Long",
"He",
"Liu",
"Sun",
"Liao",
"Wang",
"Wang",
"Zheng",
"Zhao",
"Zhang",
"Rich",
"Zhang",
"Cao",
"Xie"
] | [
"Westlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.\nResearch Center for Industries of the Future, Westlake University, Hangzhou, China.\nKey Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China.\nInstitute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China.\nSchool of Life Sciences, Westlake University, Hangzhou, China.",
"Westlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.\nResearch Center for Industries of the Future, Westlake University, Hangzhou, China.\nSchool of Life Sciences, Westlake University, Hangzhou, China.\nArtificial Intelligence Drug Design Core Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.",
"Westlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.\nResearch Center for Industries of the Future, Westlake University, Hangzhou, China.\nKey Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China.\nInstitute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China.\nSchool of Life Sciences, Westlake University, Hangzhou, China.",
"School of Life Sciences, Westlake University, Hangzhou, China.",
"Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.",
"Westlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.\nSchool of Medicine, Zhejiang University, Hangzhou, China.",
"Westlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.\nResearch Center for Industries of the Future, Westlake University, Hangzhou, China.\nSchool of Life Sciences, Westlake University, Hangzhou, China.\nArtificial Intelligence Drug Design Core Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.",
"Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.",
"Westlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.\nResearch Center for Industries of the Future, Westlake University, Hangzhou, China.\nSchool of Life Sciences, Westlake University, Hangzhou, China.\nArtificial Intelligence Drug Design Core Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.",
"Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.",
"Westlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.\nResearch Center for Industries of the Future, Westlake University, Hangzhou, China.\nKey Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China.\nInstitute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China.\nSchool of Life Sciences, Westlake University, Hangzhou, China.",
"Westlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.\nResearch Center for Industries of the Future, Westlake University, Hangzhou, China.\nSchool of Life Sciences, Westlake University, Hangzhou, China.\nArtificial Intelligence Drug Design Core Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.",
"University of Pittsburgh Medical Center Hillman Cancer Center, Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.",
"School of Life Sciences, Westlake University, Hangzhou, China.",
"Westlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China. [email protected].\nResearch Center for Industries of the Future, Westlake University, Hangzhou, China. [email protected].\nSchool of Life Sciences, Westlake University, Hangzhou, China. [email protected].\nArtificial Intelligence Drug Design Core Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China. [email protected].",
"Westlake Disease Modeling Laboratory, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China. [email protected].\nResearch Center for Industries of the Future, Westlake University, Hangzhou, China. [email protected].\nKey Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China. [email protected].\nInstitute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, China. [email protected].\nSchool of Life Sciences, Westlake University, Hangzhou, China. [email protected]."
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39418599 | 360 | Access Barriers to Anti-CD19+ CART-Cell Therapy for NHL Across a Community Transplant and Cellular Therapy Network. | We analyzed access barriers to anti-CD19+ chimeric antigen receptor T-cells (CART) for non-Hodgkin lymphoma (NHL) within a community-based transplant and cell therapy network registry. 357 intended recipients of FDA-approved anti-CD19+ CART were identified in the study period (2018 to 2022). Results showed that the median age at referral was 61 years, referral year was 2018 (4%), 2019 (14%), 2020 (18%), 2021 (26%), and 2022 (38%). Diagnoses were diffuse large B-cell (69%), follicular (13%), follicular/large (7%), mantle cell (4%), or other (7%). CART products infused were Axi-cel (62%), Tisa-cel (16%), Brexu-cel (13%) and Liso-cel (9%). 182 patients were infused with CART. The median durations between referral to consultation, consultation to apheresis, and collection to infusion were 11, 107, and 32 days, respectively. The median duration from consultation to CART infusion declined steadily from 207 days in 2019 to 108 days in 2022. [P <0.0001] 124 patients (41%) did not receive CART mostly for disease progression (34%) or poor health (15%). Multivariable logistic regression showed no significant differences in demographic, financial, or social determinants compared to those receiving CART. Notably, the proportion of ineligible patients declined from 53% in 2018-2020 to 34% by 2021-2022 [P=0.001]. In conclusion, 41% of community patients were unable to access timely CART therapy for NHL, mostly related to attrition from disease-related causes while overall time to infusion exceeded four months. Time to infusion as well as the proportion receiving CART improved over time. Reducing time to apheresis, early referral, and careful attention to salvage/bridging strategies are necessary. | [
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] | 2024-10-18 | 1 | 39418599 | [
"CART infusion",
"CART",
"timely CART therapy",
"non-Hodgkin lymphoma",
"non-Hodgkin",
"FDA-approved anti-CD19+ CART",
"community patients",
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"overall time",
"CART products",
"ineligible patients",
"referral",
"Time",
"time",
"disease progression",
"consultation",
"infusion",
"Multivariable logistic regression",
"referral year",
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"access barriers",
"13%",
"14%",
"15%",
"16%",
"18%",
"26%",
"34%",
"38%",
"4%"
] | [] | 0 | 10.1182/bloodadvances.2024014171 | [
"Battiwalla",
"Tees",
"Flinn",
"Pantin",
"Berdeja",
"Gregory",
"Maris",
"Bhushan",
"Vance",
"Mathews",
"Bachier",
"Shaughnessy",
"Ramakrishnan",
"Malik",
"Mori",
"Martin",
"Billups",
"Blunk",
"LeMaistre",
"Majhail"
] | [
"Sarah Cannon Transplant and Cellular Therapy Network, HCA Healthcare, Nashville, Tennessee, United States.",
"Sarah Cannon Transplant and Cellular Therapy Network; 3. Presbyterian/St. Luke's Medical Center and Colorado Blood Cancer Institute, United States.",
"Tennessee Oncology and OneOncology, Nashville, Tennessee, United States.",
"Sarah Cannon Transplant and Cellular Therapy Network, Nashville, Tennessee, United States.",
"Tennessee Oncology, nashville, Tennessee, United States.",
"Sarah Cannon Transplant and Cellular Therapy Network; Presbyterian/St. Luke's Medical Center and Colorado Blood Cancer Institute, United States.",
"Sarah Cannon Transplant and Cellular Therapy Network; Presbyterian/St. Luke's Medical Center and Colorado Blood Cancer Institute, United States.",
"Sarah Cannon Blood Cancer Network, DALLAS, Texas, United States.",
"Sarah Cannon Transplant and Cellular Therapy Network, Dallas, Texas, United States.",
"Sarah Cannon Transplant and Cellular Therapy Network; Medical City Dallas Hospital and Texas Oncology, United States.",
"Sarah Cannon Transplant and Cellular Therapy Network; Methodist Hospital, United States.",
"Sarah Cannon Transplant and Cellular Therapy Network; Methodist Hospital, United States.",
"Sarah Cannon Transplant and Cellular Therapy Network; St. David's South Austin Medical Center, United States.",
"Sarah Cannon Transplant and Cellular Therapy Network;6. St. David's South Austin Medical Center, United States.",
"AdventHealth Orlando, Orlando, Florida, United States.",
"Genospace, Inc., Kingston Springs, Tennessee, United States.",
"Sarah Cannon Transplant and Cellular Therapy Network, Nashville, Tennessee, United States.",
"Sarah Cannon Transplant and Cellular Therapy Network, United States.",
"Sarah Cannon Transplant and Cellular Therapy Network, United States.",
"Tristar Centennial Medical Center, United States."
] | [
"39418599"
] | [] | 6.505301 | 5.362734 |
39417976 | 361 | Neoadjuvant Chemotherapy for Adults with Osteogenic Sarcoma. | Osteosarcoma is the most common primary malignant bone tumor in adolescents and adults. The 5-year survival rate is 65% when localized; however, survival drops dramatically to 10-20% in cases of metastatic disease. Therapy for osteosarcoma saw its first significant advancement in the 1970-80's, with the introduction of our current standard of care, consisting of the neo/adjuvant treatment regimen methotrexate, doxorubicin (Adriamycin), and cisplatin (collectively referred to as MAP) and surgical resection. Since MAP, development of a better therapeutic approach has stalled, creating a plateau in patient outcomes that has persisted for 40 years. Despite substantial research into a variety of pathways for novel treatment options, clinical trials have not produced sizeable improvements in outcomes. In this article, we discuss our current neoadjuvant standard of care therapy, followed by a review of contemporary therapeutic options, including tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), monoclonal antibodies (mAbs), and chimeric antigen receptor (CAR) T cells. Lastly, we consider the challenges hindering the success of novel treatment options and future research directions. | [
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"novel treatment options",
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"immune checkpoint inhibitors",
"patient outcomes",
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] | [
"Chimeric antigen receptor T cells",
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"Immunotherapy",
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"Osteosarcoma",
"Receptor tyrosine kinases",
"Systemic therapy"
] | 0 | 10.1007/s11864-024-01269-2 | [
"Robinson",
"Davis"
] | [
"Vanderbilt-Ingram Cancer Center, 2220 Pierce Ave, PRB 777, Nashville, TN, 37232, USA.",
"Vanderbilt-Ingram Cancer Center, 2220 Pierce Ave, PRB 777, Nashville, TN, 37232, USA. [email protected]."
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] | [] | 10.578568 | 6.359746 |
39417449 | 362 | CAR-T therapy for gastrointestinal cancers: current status, challenges, and future directions. | Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary immunotherapeutic strategy that has shown efficacy in hematological malignancies. However, its application in solid tumors, particularly gastrointestinal cancers, faces significant challenges. These include the selection of target antigens, the complexity of the tumor microenvironment, and safety and toxicity concerns. This review provides a current overview of CAR-T therapy in various gastrointestinal cancers, such as esophageal, gastric, colorectal, pancreatic, and liver cancers. It discusses the limitations and future directions of CAR-T therapy in this context. This review highlights innovative strategies, including novel target antigens, multispecific CAR-T cells, armored CAR-T cells, and the development of universal CAR-T cells. These insights aim to inform ongoing research and foster advancements in CAR-T therapy for gastrointestinal cancers. | [
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"significant challenges",
"CAR) T-cell therapy",
"a revolutionary immunotherapeutic strategy",
"efficacy",
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"esophageal, gastric, colorectal, pancreatic, and liver cancers",
"a current overview",
"This review",
"the complexity",
"the limitations",
"the selection",
"These insights",
"the development"
] | [] | 0 | 10.1590/1414-431X2024e13640
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10.1007/s11899-023-00687-7 | [
"Li",
"Huang",
"Zhou",
"Cheng",
"Wang",
"Wang"
] | [
"Department of Gastrointestinal Surgery, Zhongshan City People's Hospital, Zhongshan, Guangdong, China.",
"Department of Gastrointestinal Surgery, Zhongshan City People's Hospital, Zhongshan, Guangdong, China.",
"Department of Gastrointestinal Surgery, Zhongshan City People's Hospital, Zhongshan, Guangdong, China.",
"Department of Gastrointestinal Surgery, Zhongshan City People's Hospital, Zhongshan, Guangdong, China.",
"Department of Gastrointestinal Surgery, Zhongshan City People's Hospital, Zhongshan, Guangdong, China.",
"Department of Gastrointestinal Surgery, Zhongshan City People's Hospital, Zhongshan, Guangdong, China."
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39417342 | 363 | Hemophagocytic lymphohistiocytosis in a patient with Epstein-Barr virus-positive diffuse large B-cell lymphoma treated with chimeric antigen receptor T-cell therapy. | With the advent of chimeric antigen receptors T-cell therapy, understanding their role in the development of hemophagocytic lymphohistiocytosis has become increasingly complex. We describe a case of a young patient with Epstein-Barr virus-positive diffuse large B-cell lymphoma, who was treated with axicabtagene ciloleucel. The patient developed progressive cytopenia and, on Day 73 post-infusion, met criteria for hemophagocytic lymphohistiocytosis. Bone marrow evaluation revealed hemophagocytosis without evidence of clonal B cells. The patient was treated with tocilizumab, dexamethasone, etoposide and anakinra, which eventually led to improvement. Unfortunately, the patient succumbed to an infection. Disease progression was confirmed posthumously.This case report explores the differential diagnosis of hyperinflammatory syndromes following chimeric antigen receptor T-cell therapy and highlights the reduced efficacy of this treatment in patients with a T-cell/histiocyte-rich background.
Lymphoma is an aggressive type of blood cancer that is typically treated with chemotherapy. However, the disease sometimes persists despite the initial treatment and requires new therapeutic options. A novel therapy that uses the patient’s own immune system, specifically a type of white blood cell called T lymphocytes, has recently been developed. These cells can be genetically modified to enhance recognition of cancer cells by expressing chimeric antigen receptors (CARs).CAR T-cell treatment is highly effective; however, it massively activates the patient’s immune system. This can lead to hyperinflammatory complications, including hemophagocytic lymphohistiocytosis, which is frequently fatal. This complication can arise from infections, cancer, genetic alterations or new immunotherapies.We present a case of hemophagocytic lymphohistiocytosis after CAR T-cell therapy, discuss the underlying biology, differential diagnosis and treatment options for this rare complication. | [
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] | [
"CAR t-cell therapy",
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"hemophagocytic lymphohistiocytosis",
"immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome",
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] | 0 | 10.1080/1750743X.2024.2409622
10.1002/cam4.4198
10.1182/blood.2020009148
10.1038/s41591-022-01916-x
10.1016/j.lrr.2014.05.004
10.1177/1093526617699137
10.1002/hon.3153
10.1038/nrclinonc.2017.148
10.1016/j.jtct.2023.03.006
10.3390/cancers15215149
10.1182/blood.2023020578
10.1182/blood-2017-03-769620
10.1056/NEJMoa1707447
10.1056/NEJMoa1804980
10.1016/S0140-6736(20)31366-0
10.1182/blood.2022018893
10.1159/000525576
10.1002/ajh.26668
10.3324/haematol.2022.281455
10.1080/10428194.2021.1881507
10.1002/ccr3.5209
10.1111/bjh.17662
10.1182/asheducation-2013.1.605 | [
"Meireles",
"Iacoboni",
"Moço",
"Ramos",
"Brás",
"Azevedo",
"Rodrigues",
"Moreira",
"Mariz"
] | [
"Department of Hematology & Bone Marrow Transplantation of Instituto Português de Oncologia do Porto, E.P.E (IPO-Porto), 04200, Porto, Portugal.\nClinical Oncology Group, IPO Porto Research Center (CI-IPOP), Instituto Português de Oncologia do Porto (IPO Porto), 04200, Porto, Portugal.\nPorto Comprehensive Cancer Centre (Porto.CCC) & RISE@CI-IPOP (Health Research Network), 04200, Porto, Portugal.",
"Department of Pathological Anatomy of IPO-Porto, 04200, Porto, Portugal.\nDepartment of Hematology, Experimental Hematology, Vall d'Hebron Institute of Oncology, University Hospital Vall d'Hebron, 08035, Barcelona, Spain.\nDepartment of Medicine, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain.",
"Department of Hematology & Bone Marrow Transplantation of Instituto Português de Oncologia do Porto, E.P.E (IPO-Porto), 04200, Porto, Portugal.",
"Department of Hematology & Bone Marrow Transplantation of Instituto Português de Oncologia do Porto, E.P.E (IPO-Porto), 04200, Porto, Portugal.",
"Department of Hematology & Bone Marrow Transplantation of Instituto Português de Oncologia do Porto, E.P.E (IPO-Porto), 04200, Porto, Portugal.",
"Department of Pathological Anatomy of IPO-Porto, 04200, Porto, Portugal.",
"Department of Pathological Anatomy of IPO-Porto, 04200, Porto, Portugal.",
"Department of Hematology & Bone Marrow Transplantation of Instituto Português de Oncologia do Porto, E.P.E (IPO-Porto), 04200, Porto, Portugal.\nClinical Oncology Group, IPO Porto Research Center (CI-IPOP), Instituto Português de Oncologia do Porto (IPO Porto), 04200, Porto, Portugal.\nPorto Comprehensive Cancer Centre (Porto.CCC) & RISE@CI-IPOP (Health Research Network), 04200, Porto, Portugal.",
"Department of Hematology & Bone Marrow Transplantation of Instituto Português de Oncologia do Porto, E.P.E (IPO-Porto), 04200, Porto, Portugal."
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39414947 | 364 | New horizons in our understanding of precursor multiple myeloma and early interception. | Multiple myeloma is an incurable plasma cell malignancy that evolves over decades through the selection and malignant transformation of monoclonal plasma cells. The evolution from precursor states to symptomatic disease is characterized by an increasing complexity of genomic alterations within the plasma cells and a remodelling of the microenvironment towards an immunosuppressive state. Notably, in patients with advanced disease, similar mechanisms of tumour escape and immune dysfunction mediate resistance to modern T cell-based therapies, such as T cell-engaging bispecific antibodies and chimeric antigen receptor (CAR)-T cells. Thus, an increasing number of clinical trials are assessing the efficiency and safety of these therapies in individuals with newly diagnosed multiple myeloma and high-risk smoldering multiple myeloma. In this Review, we summarize the current knowledge about tumour intrinsic and extrinsic processes underlying progression from precursor states to symptomatic myeloma and discuss the rationale for early interception including the use of T cell-redirecting therapies. | [
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10.1158/1055-9965.EPI-08-0343 | [
"Cordas Dos Santos",
"Toenges",
"Bertamini",
"Alberge",
"Ghobrial"
] | [
"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.\nHarvard Medical School, Boston, MA, USA.\nBroad Institute of Harvard and MIT, Cambridge, MA, USA.",
"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.\nHarvard Medical School, Boston, MA, USA.\nBroad Institute of Harvard and MIT, Cambridge, MA, USA.",
"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.\nDepartment of Hematology, Erasmus MC Cancer Institute Rotterdam, Rotterdam, The Netherlands.",
"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.\nHarvard Medical School, Boston, MA, USA.\nBroad Institute of Harvard and MIT, Cambridge, MA, USA.",
"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].\nHarvard Medical School, Boston, MA, USA. [email protected].\nBroad Institute of Harvard and MIT, Cambridge, MA, USA. [email protected]."
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39414236 | 365 | Chimeric antigen receptor-natural killer (CAR-NK) cell immunotherapy: A bibliometric analysis from 2004 to 2023. | Chimeric antigen receptor-natural killer (CAR-NK) cells represent a breakthrough in cancer immunotherapy, making this a highly popular research area. However, comprehensive analyses of this field using bibliometric methods are rare. To our knowledge, this study has collected highest number of publications (1,259) on CAR-NK therapy from January 1, 2004, to December 31, 2023, and utilized CiteSpace and VOSviewer to analyze regions, institutions, journals, authors, and keywords to forecast the latest trends in CAR-NK therapy research. The United States and China, contributing over 60% of publications, are the primary drivers in this field. The Helmholtz Association and Harvard University are the most active institutions, with most publications appearing in Frontiers in Immunology. Winfried S. Wels is the most prolific author, while EL Liu is the most frequently co-cited author. "Immunotherapy," "T-cells," and "Cancer" are the most extensively covered topics in CAR-NK therapy research. Our study reveals current CAR-NK research trends, identifies potential research hotspots, and visualizes references through bibliometric methods, providing valuable guidance for future research in this field. | [
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"The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.",
"Key Laboratory for Early Diagnosis and Biotherapy of Malignant Tumors in Children and Women in Liaoning Province, Dalian Women and Children's Medical Group, Dalian, Liaoning, China.",
"Key Laboratory for Early Diagnosis and Biotherapy of Malignant Tumors in Children and Women in Liaoning Province, Dalian Women and Children's Medical Group, Dalian, Liaoning, China."
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39413693 | 366 | Universal CAR cell therapy: Challenges and expanding applications. | Chimeric Antigen Receptor (CAR) T cell therapy has gained success in adoptive cell therapy for hematological malignancies. Although most CAR cell therapies in clinical trials or markets remain autologous, their acceptance has been limited due to issues like lengthy manufacturing, poor cell quality, and demanding cost. Consequently, "Off-the-shelf", universal CAR (UCAR) cell therapy has emerged. Current concerns with UCAR therapies revolve around side effects such as graft versus host disease (GVHD) and host versus graft response (HVGR). Preclinical research on UCAR cell therapies aims to enhance efficacy and minimize these side effects. Common approaches involve gene editing techniques to knock out T cell receptor (TCR), human leukocyte antigen (HLA), and CD52 expression to mitigate GVHD and HVGR risks. However, these methods carry drawbacks including potential genotoxicity of the edited cells. Most recently, novel editing techniques, such as epigenetic editing and RNA writer systems, have been developed to reduce the risk of GVHD and HVGR, allowing for multiplex editing at different sites. Additionally, incorporating more cell types into UCAR cell therapies, like T-cell subtypes (DNT, γδT, virus-specific T cells) and NK cells, can efficiently target tumors without triggering side effects. In addition, the limited efficacy of T cells and NK cells against solid tumors is being addressed through CAR-Macrophages. In summary, CAR cell therapy has evolved to accommodate multiple cell types while expanding applications to various diseases, including hematologic malignancies and solid tumors, which holds tremendous growth potential and is promised to improve the lives of more patients in the future. | [
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] | 2024-10-17 | 73 | 39413693 | [
"UCAR cell therapies",
"CAR cell therapy",
"adoptive cell therapy",
"T cells",
"most CAR cell therapies",
"T cell receptor",
"NK cells",
"more cell types",
"multiple cell types",
"poor cell quality",
"UCAR therapies",
"solid tumors",
"T-cell subtypes",
"side effects",
"novel editing techniques",
"universal CAR (UCAR) cell therapy",
"UCAR",
"multiplex editing",
"epigenetic editing",
"tumors",
"the edited cells",
"host disease",
"RNA writer systems",
"tremendous growth potential",
"CAR",
"various diseases",
"GVHD",
"more patients",
"hematologic malignancies",
"lengthy manufacturing"
] | [
"Cancer",
"Chimeric antigen receptor",
"Immunotherapy",
"Off-the-shelf",
"Universal cell therapy"
] | 0 | 10.1016/j.tranon.2024.102147 | [
"Wu",
"Wang",
"Jin",
"Wang"
] | [
"Department of Hematology I, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.",
"Department of Translational Medicine, Research Ward, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Hangzhou, China. Electronic address: [email protected].",
"Department of Translational Medicine, Research Ward, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Hangzhou, China. Electronic address: [email protected].",
"Department of Hematology I, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China. Electronic address: [email protected]."
] | [
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39413356 | 367 | Efficacy and Safety of Ibrutinib as Monotherapy or Combination Therapy in Relapsed/Refractory Diffuse Large B-cell Lymphoma (R/R DLBCL): A Systematic Review and Meta-analysis. | Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous disease group. Ibrutinib's monotherapy or combination therapy is effective in relapsed/refractory (R/R) DLBCL. However, the treatment response in R/R DLBCL varies from 15% to 90% with different regimens, and the tolerance remains controversial.
The efficacy and safety of ibrutinib monotherapy or combination therapy in patients with R/R DLBCL remain uncertain.
The PubMed, CBM, MEDLINE, Cochrane Library, and Embase databases were searched from their inception to July 2021.
The total complete remission rate (CRR) and overall response rate in R/R DLBCL patients treated with ibrutinib were 26% and 49%, respectively. The CRR of ibrutinib combination therapy was significantly higher than the ibrutinib monotherapy (45% vs. 19%). Moreover, the CRR of patients was 40% in double expressing lymphoma, 35% in central nervous system lymphoma, and 33% in nongerminal center B-cell-like (non-GCB) DLBCL, which was higher than the 8% in those with the GCB subtype. The pooled median PFS and overall survival were 5.57 and 10.17 months, respectively. GCB-DLBCL had the worst overall survival (5.1 months). Nevertheless, we found that combination regimens had no survival advantage compared with monotherapy ( P > 0.05), indicating that combination therapy was only a transitional treatment and bridge for chimeric antigen receptor T cells or other treatments. Moreover, 12% of patients on ibrutinib combination therapy had ≥grade 3 adverse events compared with 9% on ibrutinib monotherapy.
Ibrutinib monotherapy or combination therapy was safe and effective in treating R/R DLBCL with tolerable adverse reactions. | [
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] | [] | 0 | 10.1097/MJT.0000000000001831 | [
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"Li",
"Lv",
"Wang",
"Li"
] | [
"Jiangxi Provincial Key Laboratory of Hematological Diseases, Department of Hematology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China; and.\nDepartment of Geriatric, Yangtze River Shipping General Hospital, Wuhan, Hubei, China.",
"Jiangxi Provincial Key Laboratory of Hematological Diseases, Department of Hematology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China; and.",
"Jiangxi Provincial Key Laboratory of Hematological Diseases, Department of Hematology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China; and.",
"Jiangxi Provincial Key Laboratory of Hematological Diseases, Department of Hematology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China; and.",
"Jiangxi Provincial Key Laboratory of Hematological Diseases, Department of Hematology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China; and."
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] | 2024-10-16 | 1 | 39413160 | [
"Regulatory T cells",
"T"
] | [] | 0 | 10.1126/scitranslmed.adj9331 | [
"Rui",
"Alvarez Calderon",
"Wobma",
"Gerdemann",
"Albanese",
"Cagnin",
"McGuckin",
"Michaelis",
"Naqvi",
"Blazar",
"Tkachev",
"Kean"
] | [
"Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA.",
"Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA.\nDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.\nHarvard Medical School, Boston, MA 02115, USA.",
"Harvard Medical School, Boston, MA 02115, USA.\nDivision of Immunology, Boston Children's Hospital, Boston, MA 02215, USA.",
"Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA.\nDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.\nHarvard Medical School, Boston, MA 02115, USA.",
"Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA.\nDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.\nHarvard Medical School, Boston, MA 02115, USA.",
"Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA.",
"Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA.",
"Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA.",
"Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA.\nUniversity of British Columbia, Vancouver, BC V6T 1Z1, Canada.",
"Division of Pediatric Blood and Marrow Transplant and Cellular Therapy, University of Minnesota, Minneapolis, MN 55455, USA.",
"Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA.\nHarvard Medical School, Boston, MA 02115, USA.\nCenter for Transplantation Sciences, Massachusetts General Hospital, Boston, MA 02129, USA.",
"Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA.\nDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.\nHarvard Medical School, Boston, MA 02115, USA."
] | [
"39413160"
] | [] | 33.498951 | 7.469467 |
39411712 | 369 | Finding potential targets in cell-based immunotherapy for handling the challenges of acute myeloid leukemia. | Acute myeloid leukemia (AML) is a hostile hematological malignancy under great danger of relapse and poor long-term survival rates, despite recent therapeutic advancements. To deal with this unfulfilled clinical necessity, innovative cell-based immunotherapies have surfaced as promising approaches to improve anti-tumor immunity and enhance patient outcomes. In this comprehensive review, we provide a detailed examination of the latest developments in cell-based immunotherapies for AML, including chimeric antigen receptor (CAR) T-cell therapy, T-cell receptor (TCR)-engineered T-cell therapy, and natural killer (NK) cell-based therapies. We critically evaluate the unique mechanisms of action, current challenges, and evolving strategies to improve the efficacy and safety of these modalities. The review emphasizes how promising these cutting-edge immune-based strategies are in overcoming the inherent complexities and heterogeneity of AML. We discuss the identification of optimal target antigens, the importance of mitigating on-target/off-tumor toxicity, and the need to enhance the persistence and functionality of engineered immune effector cells. All things considered, this review offers a thorough overview of the rapidly evolving field of cell-based immunotherapy for AML, underscoring the significant progress made and the ongoing efforts to translate these innovative approaches into more effective and durable treatments for this devastating disease. | [
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10.1038/s41591-022-01880-6 | [
"Kheirkhah",
"Habibi",
"Yousefi",
"Mehri",
"Ma",
"Saleh",
"Kavianpour"
] | [
"Department of Tissue Engineering and Applied Cell Sciences, School of Medicine, Qom University of Medical Sciences, Qom, Iran.",
"Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran.",
"Department of Tissue Engineering and Applied Cell Sciences, School of Medicine, Qom University of Medical Sciences, Qom, Iran.",
"Department of Biotechnology, School of Paramedical Sciences, Qazvin University of Medical Sciences, Qazvin, Iran.",
"School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.\nClinical Stem Cell Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.",
"Wisconsin National Primate Research Center, University of Wisconsin Graduate School, Madison, WI, United States.",
"Department of Tissue Engineering and Applied Cell Sciences, School of Medicine, Qom University of Medical Sciences, Qom, Iran.\nCellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran."
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39409959 | 370 | Advancement and Challenges in Monitoring of CAR-T Cell Therapy: A Comprehensive Review of Parameters and Markers in Hematological Malignancies. | Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment for relapsed/refractory B-cell lymphomas. Despite its success, this therapy is accompanied by a significant frequency of adverse events, including cytokine release syndrome (CRS), immune-effector-cell-associated neurotoxicity syndrome (ICANS), or cytopenias, reaching even up to 80% of patients following CAR-T cell therapy. CRS results from the uncontrolled overproduction of proinflammatory cytokines, which leads to symptoms such as fever, headache, hypoxia, or neurological complications. CAR-T cell detection is possible by the use of flow cytometry (FC) or quantitative polymerase chain reaction (qPCR) assays, the two primary techniques used for CAR-T evaluation in peripheral blood, bone marrow (BM), and cerebrospinal fluid (CSF). State-of-the-art imaging technologies play a crucial role in monitoring the distribution and persistence of CAR-T cells in clinical trials. Still, they can also be extended with the use of FC and digital PCR (dPCR). Monitoring the changes in cell populations during disease progression and treatment gives an important insight into how the response to CAR-T cell therapy develops on a cellular level. It can help improve the therapeutic design and optimize CAR-T cell therapy to make it more precise and personalized, which is crucial to overcoming the problem of tumor relapse. | [
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"Basak"
] | [
"Department of Biochemistry and Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, 02-097 Warsaw, Poland.\nDepartment of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, 02-097 Warsaw, Poland.\nCentre for Preclinical Research, Medical University of Warsaw, 02-097 Warsaw, Poland.",
"Department of Biochemistry and Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, 02-097 Warsaw, Poland.\nDepartment of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, 02-097 Warsaw, Poland.\nCentre for Preclinical Research, Medical University of Warsaw, 02-097 Warsaw, Poland.",
"Department of Biochemistry and Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, 02-097 Warsaw, Poland.\nCentre for Preclinical Research, Medical University of Warsaw, 02-097 Warsaw, Poland.",
"Department of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, 02-097 Warsaw, Poland."
] | [
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] | [] | 6.306058 | 4.364684 |
39409909 | 371 | Measurable Residual Disease Testing in Multiple Myeloma Following T-Cell Redirecting Therapies. | Several novel T-cell-based therapies have recently become available for multiple myeloma (MM). These T-cell redirecting therapies (TRTs) include chimeric antigen receptor T-cells (CAR-T) and bispecific antibodies (BiAbs). In both clinical trial and real-world data, these therapies have demonstrated high rates of deep clinical response, and some are now approved for second-line treatment for relapsed MM. The deep and sustained clinical responses these therapies are capable of inducing will require sophisticated response monitoring to provide meaningful information for patient care. Obtaining measurable residual disease (MRD) negativity has been validated as an independent positive prognostic marker for progression-free survival (PFS) and overall survival (OS) in both newly diagnosed and relapsed refractory patients with multiple myeloma. Assessment for MRD negativity was performed in all of the trials for FDA-approved TRT. Here, we summarize pertinent data for MRD assessment following TRT in MM and provide a rationale and structured framework for conducting MRD testing post TRT. | [
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39409881 | 372 | Chondroitin Sulfate Proteoglycan 4 (CSPG4) as an Emerging Target for Immunotherapy to Treat Melanoma. | Immunotherapies, including checkpoint inhibitor antibodies, have precipitated significant improvements in clinical outcomes for melanoma. However, approximately half of patients do not benefit from approved treatments. Additionally, apart from Tebentafusp, which is approved for the treatment of uveal melanoma, there is a lack of immunotherapies directly focused on melanoma cells. This is partly due to few available targets, especially those expressed on the cancer cell surface. Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell surface molecule overexpressed in human melanoma, with restricted distribution and low expression in non-malignant tissues and involved in several cancer-promoting and dissemination pathways. Here, we summarize the current understanding of the expression and functional significance of CSPG4 in health and melanoma, and we outline immunotherapeutic strategies. These include monoclonal antibodies, antibody-drug conjugates (ADCs), chimeric-antigen receptor (CAR) T cells, and other strategies such as anti-idiotypic and mimotope vaccines to raise immune responses against CSPG4-expressing melanomas. Several showed promising functions in preclinical models of melanoma, yet few have reached clinical testing, and none are approved for therapeutic use. Obstacles preventing that progress include limited knowledge of CSPG4 function in human cancer and a lack of in vivo models that adequately represent patient immune responses and human melanoma biology. Despite several challenges, immunotherapy directed to CSPG4-expressing melanoma harbors significant potential to transform the treatment landscape. | [
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"St. John's Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King's College London, London SE1 9RT, UK.",
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"St. John's Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King's College London, London SE1 9RT, UK.\nOncology Department, Guy's and St Thomas' Hospitals, London SE1 9RT, UK.\nBreast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, King's College London, Innovation Hub, Guy's Hospital, London SE1 9RT, UK.",
"St. John's Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King's College London, London SE1 9RT, UK.\nBreast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, King's College London, Innovation Hub, Guy's Hospital, London SE1 9RT, UK.\nPeter Gorer Department of Immunobiology, Centre for Inflammation Biology and Cancer Immunology, School of Immunology and Microbial Sciences, King's College London, London SE1 9RT, UK.",
"St John's Institute of Dermatology, Guy's, King's and St. Thomas' Hospitals NHS Foundation Trust, London SE1 9RT, UK.\nDepartment of Plastic Surgery, Guy's, King's and St. Thomas' Hospitals, London SE1 9RT, UK.",
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] | [] | 10.577438 | 4.955607 |
39408896 | 373 | A Customizable Platform to Integrate CAR and Conditional Expression of Immunotherapeutics in T Cells. | The potential of chimeric antigen receptor (CAR)-based immunotherapy as a promising therapeutic approach is often hindered by the presence of highly immunosuppressive tumor microenvironments (TME). Combination therapies with either co-administration or built-in expression of additional TME-modulating therapeutic molecules to potentiate the functions of CAR-T cells can cause systemic toxicities due to the lack of control over the delivery of biologics. Here, we present a proof-of-concept engineered platform in human Jurkat T cells that combines CAR with a therapeutic gene circuit capable of sensing | [
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10.1074/jbc.M110.160077 | [
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39408696 | 374 | Revolutionizing CAR T-Cell Therapies: Innovations in Genetic Engineering and Manufacturing to Enhance Efficacy and Accessibility. | Chimeric antigen receptor (CAR) T-cell therapy has achieved notable success in treating hematological cancers but faces significant challenges in solid-tumor treatment and overall efficacy. Key limitations include T-cell exhaustion, tumor relapse, immunosuppressive tumor microenvironments (TME), immunogenicity, and antigen heterogeneity. To address these issues, various genetic engineering strategies have been proposed. Approaches such as overexpression of transcription factors or metabolic armoring and dynamic CAR regulation are being explored to improve CAR T-cell function and safety. Other efforts to improve CAR T-cell efficacy in solid tumors include targeting novel antigens or developing alternative strategies to address antigen diversity. Despite the promising preclinical results of these solutions, challenges remain in translating CAR T-cell therapies to the clinic to enable economically viable access to these transformative medicines. The efficiency and scalability of autologous CAR T-cell therapy production are hindered by traditional, manual processes which are costly, time-consuming, and prone to variability and contamination. These high-cost, time-intensive processes have complex quality-control requirements. Recent advancements suggest that smaller, decentralized solutions such as microbioreactors and automated point-of-care systems could improve production efficiency, reduce costs, and shorten manufacturing timelines, especially when coupled with innovative manufacturing methods such as transposons and lipid nanoparticles. Future advancements may include harmonized consumables and AI-enabled technologies, which promise to streamline manufacturing, reduce costs, and enhance production quality. | [
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"harmonized consumables",
"Recent advancements",
"challenges",
"Future advancements",
"hematological cancers",
"manufacturing timelines",
"notable success",
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10.1002/bit.27376 | [
"Giorgioni",
"Ambrosone",
"Cometa",
"Salvati",
"Nisticò",
"Magrelli"
] | [
"Faculty of Physiology and Pharmacology \"V. Erspamer\", Sapienza Università di Roma, 00185 Rome, Italy.",
"National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, 00161 Rome, Italy.",
"National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, 00161 Rome, Italy.",
"Faculty of Pharmacy, Tor Vergata University of Rome, 00133 Rome, Italy.",
"Faculty of Pharmacy, Tor Vergata University of Rome, 00133 Rome, Italy.\nAgenzia Italiana del Farmaco, Via del Tritone 181, 00187 Rome, Italy.",
"National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, 00161 Rome, Italy."
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39407796 | 375 | Novel Immune Checkpoint Inhibitor Targets in Advanced or Metastatic Renal Cell Carcinoma: State of the Art and Future Perspectives. | Immune checkpoint inhibitors (ICI) have become the cornerstone of treatment in renal cell carcinoma (RCC), for both metastatic disease and in an adjuvant setting. However, an adaptive resistance from cancer cells may arise during ICI treatment, therefore many studies are focusing on additional immune checkpoint inhibitor pathways. Promising targets of immunotherapeutic agents under investigation include T cell immunoglobulin and ITIM domain (TIGIT), immunoglobulin-like transcript 4 (ILT4), lymphocyte activation gene-3 (LAG-3), vaccines, T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and chimeric antigen receptor (CAR) T cells. In this review of the literature, we recollect the current knowledge of the novel treatment strategies in the field of immunotherapy that are being investigated in RCC and analyze their mechanism of action, their activity and the clinical studies that are currently underway. | [
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"Medical Oncology, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.\nDepartment of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy.",
"Medical Oncology, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.\nDepartment of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy.",
"Medical Oncology, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.\nDepartment of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy.",
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"Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy.\nDivision of Urology, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.",
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39406935 | 376 | Transient CAR T cells with specificity to oncofetal glycosaminoglycans in solid tumors. | Glycosaminoglycans are often deprioritized as targets for synthetic immunotherapy due to the complexity of glyco-epitopes and limited options for obtaining specific subtype binding. Solid tumors express proteoglycans that are modified with oncofetal chondroitin sulfate (CS), a modification normally restricted to the placenta. Here, we report the design and functionality of transient chimeric antigen receptor (CAR) T cells with selectivity to oncofetal CS. Following expression in T cells, the CAR could be "armed" with recombinant VAR2CSA lectins (rVAR2) to target tumor cells expressing oncofetal CS. While unarmed CAR T cells remained inactive in the presence of target cells, VAR2-armed CAR T cells displayed robust activation and the ability to eliminate diverse tumor cell types in vitro. Cytotoxicity of the CAR T cells was proportional to the concentration of rVAR2 available to the CAR, offering a potential molecular handle to finetune CAR T cell activity. In vivo, armed CAR T cells rapidly targeted bladder tumors and increased the survival of tumor-bearing mice. Thus, our work indicates that cancer-restricted glycosaminoglycans may be exploited as potential targets for CAR T cell therapy. | [
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] | 2024-10-16 | 49 | 39406935 | [
"T cells",
"CAR T cell activity",
"CAR T cell therapy",
"armed CAR T cells",
"unarmed CAR T cells",
"tumor cells",
"target cells",
"diverse tumor cell types",
"potential targets",
"VAR2-armed CAR T cells",
"bladder tumors",
"oncofetal CS",
"Solid tumors",
"CAR",
"oncofetal chondroitin sulfate",
"transient chimeric antigen receptor",
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"limited options",
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"synthetic immunotherapy",
"CS",
"chondroitin sulfate",
"robust activation",
"rVAR2",
"tumor-bearing mice",
"functionality",
"cancer-restricted glycosaminoglycans",
"proteoglycans",
"a potential molecular handle"
] | [
"CAR T Cells",
"Chondroitin Sulfate",
"Immunotherapy",
"Oncofetal CS",
"Solid Tumor"
] | 0 | 10.1038/s44321-024-00153-8 | [
"Khazamipour",
"Oo",
"Al-Nakouzi",
"Marzban",
"Khazamipour",
"Roberts",
"Farivar",
"Moskalev",
"Lo",
"Ghaidi",
"Nelepcu",
"Moeen",
"Truong",
"Dagil",
"Choudhary",
"Gustavsson",
"Zhai",
"Heitzender",
"Salanti",
"Sorensen",
"Daugaard"
] | [
"Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.\nVancouver Prostate Centre, Vancouver Coastal Health Research Institutes, Vancouver, BC, Canada.",
"Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.\nVancouver Prostate Centre, Vancouver Coastal Health Research Institutes, Vancouver, BC, Canada.\nMolecular Pathology & Cell Imaging Laboratory, Vancouver Coastal Health Research Institutes, Vancouver, BC, Canada.",
"Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.\nVancouver Prostate Centre, Vancouver Coastal Health Research Institutes, Vancouver, BC, Canada.",
"Vancouver Prostate Centre, Vancouver Coastal Health Research Institutes, Vancouver, BC, Canada.",
"Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.\nVancouver Prostate Centre, Vancouver Coastal Health Research Institutes, Vancouver, BC, Canada.",
"Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.\nVancouver Prostate Centre, Vancouver Coastal Health Research Institutes, Vancouver, BC, Canada.",
"Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.\nVancouver Prostate Centre, Vancouver Coastal Health Research Institutes, Vancouver, BC, Canada.",
"Vancouver Prostate Centre, Vancouver Coastal Health Research Institutes, Vancouver, BC, Canada.",
"Vancouver Prostate Centre, Vancouver Coastal Health Research Institutes, Vancouver, BC, Canada.",
"Vancouver Prostate Centre, Vancouver Coastal Health Research Institutes, Vancouver, BC, Canada.",
"Vancouver Prostate Centre, Vancouver Coastal Health Research Institutes, Vancouver, BC, Canada.",
"Vancouver Prostate Centre, Vancouver Coastal Health Research Institutes, Vancouver, BC, Canada.",
"Vancouver Prostate Centre, Vancouver Coastal Health Research Institutes, Vancouver, BC, Canada.",
"Centre for Translational Medicine and Parasitology at Department for Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark.\nVAR2 Pharmaceuticals ApS, Copenhagen, Denmark.",
"Centre for Translational Medicine and Parasitology at Department for Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark.\nVAR2 Pharmaceuticals ApS, Copenhagen, Denmark.",
"Centre for Translational Medicine and Parasitology at Department for Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark.\nVAR2 Pharmaceuticals ApS, Copenhagen, Denmark.",
"Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.\nVancouver Prostate Centre, Vancouver Coastal Health Research Institutes, Vancouver, BC, Canada.",
"Division of Pediatric Hematology/Oncology/Stem Cell Transplantation and Regenerative Medicine, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.",
"Centre for Translational Medicine and Parasitology at Department for Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark.\nVAR2 Pharmaceuticals ApS, Copenhagen, Denmark.",
"VAR2 Pharmaceuticals ApS, Copenhagen, Denmark.\nDepartment of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.\nDepartment of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.",
"Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada. [email protected].\nVancouver Prostate Centre, Vancouver Coastal Health Research Institutes, Vancouver, BC, Canada. [email protected].\nMolecular Pathology & Cell Imaging Laboratory, Vancouver Coastal Health Research Institutes, Vancouver, BC, Canada. [email protected].\nVAR2 Pharmaceuticals ApS, Copenhagen, Denmark. [email protected]."
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39404622 | 377 | Preclinical Development of T Cells Engineered to Express a T-Cell Antigen Coupler Targeting Claudin 18.2-Positive Solid Tumors. | The T-cell antigen coupler (TAC) is a chimeric receptor that facilitates tumor antigen-specific activation of T cells by co-opting the endogenous T-cell receptor complex in the absence of tonic signaling. Previous data demonstrate that the TAC affords T cells with the ability to induce durable and safe antitumor responses in preclinical models of hematologic and solid tumors. In this study, we describe the preclinical pharmacology and safety of an autologous Claudin 18.2 (CLDN18.2)-directed TAC T-cell therapy, TAC01-CLDN18.2, in preparation for a phase I/II clinical study in subjects with CLDN18.2-positive solid tumors. Following a screen of putative TAC constructs, the specificity, activity, and cytotoxicity of TAC T cells expressing the final CLDN18.2-TAC receptor were evaluated in vitro and in vivo using gastric, gastroesophageal, and pancreatic tumor models as well as human cells derived from normal tissues. CLDN18.2-specific activity and cytotoxicity of CLDN18.2-TAC T cells were observed in coculture with various 2D tumor cultures naturally expressing CLDN18.2 as well as tumor spheroids. These effects occurred in models with low antigen levels and were positively associated with increasing CLDN18.2 expression. CLDN18.2-TAC T cells effectively eradicated established tumor xenografts in mice in the absence of observed off-target or on-target/off-tumor effects, elicited durable efficacy in recursive killing and tumor rechallenge experiments, and remained unreactive in coculture with human cells representing vital organs. Thus, the data demonstrate that CLDN18.2-TAC T cells can induce a specific and long-lasting antitumor response in various CLDN18.2-positive solid tumor models without notable TAC-dependent toxicities, supporting the clinical development of TAC01-CLDN18.2. | [
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] | 2024-10-15 | 41 | 39404622 | [
"TAC T cells",
"T cells",
"human cells",
"pancreatic tumor models",
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"putative TAC constructs",
"tumor",
"tumor rechallenge experiments",
"various 2D tumor cultures",
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"elicited durable efficacy",
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"CLDN18.2-TAC",
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"hematologic and solid tumors",
"The T-cell antigen coupler",
"the final CLDN18.2-TAC receptor",
"recursive killing",
"CLDN18.2-specific activity",
"cytotoxicity"
] | [] | 0 | 10.1158/2326-6066.CIR-24-0138 | [
"Xu",
"Wang",
"Ip",
"Randhawa",
"Benatar",
"Prosser",
"Lal",
"Khan",
"Nitya-Nootan",
"Thakor",
"MacGregor",
"Hayes",
"Vucicevic",
"Mathew",
"Sengupta",
"Helsen",
"Bader"
] | [
"Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada.",
"Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada.",
"Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada.",
"Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada.",
"Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada.",
"Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada.",
"Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada.",
"Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada.",
"Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada.",
"Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada.",
"Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada.",
"Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada.",
"Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada.",
"Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada.",
"Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada.",
"Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada.",
"Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada."
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39403625 | 378 | APOBEC3B expression in 293T viral producer cells drives mutations in chimeric antigen receptors and reduces CAR T cell efficacy. | Chimeric antigen receptor (CAR) T cells are a clinically approved therapy for blood cancers. To produce clinical-grade CAR T cells, a retroviral or lentiviral vector is used to deliver the CAR and associated genes to patient T cells. Apolipoprotein B editing enzyme, catalytic polypeptide 3 (APOBEC3) enzymes are known to be upregulated after transfection and retroviral infection and to deaminate cytidine to uracil in nucleic acids, resulting in cytidine-to-thymine mutations in DNA. Here, we hypothesized that APOBEC3 enzymes, induced during the production of CAR T cells, impact the efficacy of the resulting CAR T cells. We demonstrated that APOBEC3 family member APOBEC3B was upregulated at the RNA and protein levels after transfection of HEK293T cells with plasmids to make lentivirus, and that APOBEC3 signature mutations were present in the CAR construct. APOBEC3B overexpression in HEK293T cells led to further mutations in the resulting CAR T cells, and significantly decreased CAR T cell killing. APOBEC3B knockout in HEK293T cells led to reduced mutations in the CAR construct and significantly increased in CAR T cell killing. These results suggest that generation of CAR-expressing viruses from producer cell lines deficient in genome-modifying proteins such as APOBEC3B could enhance the quality of CAR T cell production. | [
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39402681 | 379 | Nanotechnology for boosting ovarian cancer immunotherapy. | Ovarian cancer, often referred to as the "silent killer," is notoriously difficult to detect in its early stages, leading to a poor prognosis for many patients. Diagnosis is often delayed until the cancer has advanced, primarily due to its ambiguous and frequently occurring clinical symptoms. Ovarian cancer leads to more deaths than any other cancer of the female reproductive system. The main reasons for the high mortality rates include delayed diagnosis and resistance to treatment. As a result, there is an urgent need for improved diagnostic and treatment options for ovarian cancer. The standard treatments typically involve debulking surgery along with platinum-based chemotherapies. Among patients with advanced-stage cancer who initially respond to current therapies, 50-75% experience a recurrence. Recently, immunotherapy-based approaches to enhance the body's immune response to combat tumor growth have shown promise. Immune checkpoint inhibitors have shown promising results in treating other types of tumors. However, in ovarian cancer, only a few of these inhibitors have been effective because the tumor's environment suppresses the immune system and creates barriers for treatment. This hampers the effectiveness of existing immunotherapies. Nonetheless, advanced immunotherapy techniques and delivery systems based on nanotechnology hold promise for overcoming these challenges. | [
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] | 2024-10-15 | 96 | 39402681 | [
"Ovarian cancer",
"ovarian cancer",
"Immune checkpoint inhibitors",
"delivery systems",
"advanced immunotherapy techniques",
"tumor growth",
"treatment",
"delayed diagnosis",
"existing immunotherapies",
"promising results",
"other types",
"tumors",
"current therapies",
"debulking surgery",
"advanced-stage cancer",
"many patients",
"any other cancer",
"more deaths",
"improved diagnostic and treatment options",
"clinical symptoms",
"promise",
"immunotherapy-based approaches",
"Diagnosis",
"the immune system",
"nanotechnology",
"patients",
"platinum-based chemotherapies",
"the female reproductive system",
"the cancer",
"the high mortality rates"
] | [
"Adoptive cell therapy",
"Chimeric antigen receptor T-cell therapy",
"Clinical trials",
"Immune checkpoint blockade",
"Myeloid-derived suppressor cells",
"Ovarian cancer",
"Photodynamic therapy",
"Photothermal therapy",
"Regulatory T cells",
"Tumor-associated macrophages"
] | 0 | 10.1186/s13048-024-01507-z | [
"Kaur",
"Singh",
"Mishra",
"Singh",
"Singh"
] | [
"Department of Microbiology, Biochemistry and Immunology, Cancer Health Equity Institute, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA, 30310, USA.",
"Department of Microbiology, Biochemistry and Immunology, Cancer Health Equity Institute, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA, 30310, USA.",
"Cancer Biology Research and Training, Department of Biological Sciences, Alabama State University, Montgomery, AL, 36014, USA.",
"Department of Microbiology, Biochemistry and Immunology, Cancer Health Equity Institute, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA, 30310, USA.\nCancer Health Equity Institute, Morehouse School of Medicine, Atlanta, GA, 30310, USA.",
"Department of Microbiology, Biochemistry and Immunology, Cancer Health Equity Institute, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA, 30310, USA. [email protected].\nCancer Health Equity Institute, Morehouse School of Medicine, Atlanta, GA, 30310, USA. [email protected]."
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] | [] | 11.144118 | 4.983685 |
39400611 | 380 | Revolutionizing cancer treatment: an in-depth exploration of CAR-T cell therapies. | Cancer is a leading cause of fatality worldwide. Due to the heterogeneity of cancer cells the effectiveness of various conventional cancer treatment techniques is constrained. Thus, researchers are diligently investigating therapeutic approaches like immunotherapy for effective tumor managements. Immunotherapy harnesses the inherent potential of patient's immune system to achieve desired outcomes. Within the realm of immunotherapy, CAR-T (Chimeric Antigen Receptor T) cells, emerges as a revolutionary innovation for cancer therapy. The process of CAR-T cell therapy entails extracting the patient's T cells, altering them with customized receptors designed to specifically recognize and eradicate the tumor cells, and then reinfusing the altered cells into the patient's body. Although there has been significant progress with CAR-T cell therapy in certain cases of specific B-cell leukemia and lymphoma, its effectiveness is hindered in hematological and solid tumors due to the challenges such as severe toxicities, restricted tumor infiltration, cytokine release syndrome and antigen escape. Overcoming these obstacles requires innovative approaches to design more effective CAR-T cells, which require a competent and diverse team to develop and implement. This comprehensive review addresses numerous therapeutic issues and provides a strategic solution while providing a deep understanding of the structural intricacies and production processes of CAR-T cells. In addition, this review explores the practical aspects of CAR-T cell therapy in clinical settings. | [
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] | 2024-10-14 | 179 | 39400611 | [
"cancer cells",
"cancer therapy",
"CAR-T cell therapy",
"effective tumor managements",
"tumor infiltration",
"CAR-T cells",
"various conventional cancer treatment techniques",
"therapeutic approaches",
"numerous therapeutic issues",
"specific B-cell leukemia",
"the tumor cells",
"Cancer",
"Chimeric Antigen Receptor T",
"innovative approaches",
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"severe toxicities",
"customized receptors",
"certain cases",
"desired outcomes",
"hematological and solid tumors",
"patients immune system",
"clinical settings",
"significant progress",
"lymphoma"
] | [
"Cancer",
"Chimeric antigen receptor",
"Genetic engineering",
"Immunotherapy",
"Solid tumors"
] | 0 | 10.1007/s12032-024-02491-6
10.1056/NEJMoa1804980
10.1155/2021/6644685
10.1155/2018/2386187
10.1126/scitranslmed.3002842
10.1155/2021/6630295
10.1038/s41591-024-02893-z
10.1053/j.seminhematol.2018.08.008
10.1007/978-94-007-7359-2_12
10.1158/2159-8290.CD-24-0102
10.1172/jci.insight.126345
10.1038/s41572-020-00240-3
10.3389/fimmu.2016.00690
10.1155/2019/1092587 | [
"Kandav",
"Chandel"
] | [
"Chandigarh College of Pharmacy, Chandigarh Group of Colleges, Landran, Sahibzada Ajit Singh Nagar, Punjab, 140307, India. [email protected].",
"Chandigarh College of Pharmacy, Chandigarh Group of Colleges, Landran, Sahibzada Ajit Singh Nagar, Punjab, 140307, India."
] | [
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39399500 | 381 | Transcriptional rewiring in CD8 | T cells engineered to express chimeric-antigen receptors (CAR-T cells) can effectively control relapsed and refractory haematological malignancies in the clinic. However, the successes of CAR-T cell therapy have not been recapitulated in solid tumours due to a range of barriers such as immunosuppression, poor infiltration, and tumour heterogeneity. Numerous strategies are being developed to overcome these barriers, which include improving culture conditions and manufacturing protocols, implementing novel CAR designs, and novel approaches to engineering the T cell phenotype. In this review, we describe the various emerging strategies to improve CAR T cell therapy for solid tumours. We specifically focus on new strategies to modulate cell function and fate that have precipitated from the growing knowledge of transcriptional circuits driving T cell differentiation, with the ultimate goal of driving more productive anti-tumour T cell immunity. Evidence shows that enrichment of particular phenotypic subsets of T cells in the initial cell product correlates to improved therapeutic responses and clinical outcomes. Furthermore, T cell exhaustion and poor persistence are major factors limiting therapeutic efficacy. The latest preclinical work shows that targeting specific master regulators and transcription factors can overcome these key barriers, resulting in superior T cell therapeutic products. This can be achieved by targeting key transcriptional circuits promoting memory-like phenotypes or sustaining key effector functions within the hostile tumour microenvironment. Additional discussion points include emerging considerations for the field such as (i) targeting permutations of transcription factors, (ii) transient expression systems, (iii) tissue specificity, and (iv) expanding this strategy beyond CAR-T cell therapy and cancer. | [
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"School of Biomedical Sciences, The University of Western Australia, Perth, WA, Australia.\nTelethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, Australia.",
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39396632 | 382 | Addition of Nivolumab Tailored by Expansion of CAR-T Cells in Patients with Stable/Progressive Large B Cell Lymphoma at Lymphodepletion-A Phase 2, Prospective Interventional Study. | Patients with large B-cell lymphoma (LBCL) in stable or progressive disease (SD/PD) at lymphodepletion prior to chimeric antigen receptor T cell (CAR-T) therapy have an inferior outcome. we hypothesized that enhancing in-vivo expansion of CAR-T cells could overcome this grim prognosis leading to improved outcomes. We conducted a phase 2 prospective trial (NCT05385263) investigating the addition of nivolumab to enhance CAR-T cell expansion and response in patients with SD/PD-LBCL. Eligible patients received 1 dose of nivolumab between day +5 and +9 post CAR-T infusion. An additional dose of nivolumab was administered on day +19 only to patients whose CAR-T cell levels in peripheral blood were below 100 cells/µL at day +7. Twenty patients were enrolled and received anti-CD19 CAR-T (Axicabtagene ciloleucel, n = 12; tisagenlecleucel, n = 8). Eight were ineligible to receive nivolumab due to active CAR-T-associated toxicities. Overall, the protocol was safe. One-month PET-CT showed an 84% overall response rate (complete response, 53%). The cumulative incidence of progression-free survival at 6 and 12 months were 50% (95% CI 36%-64%) and 42% (95% CI 26%-58%), respectively. The cumulative incidence of overall survival at 6 and 12 months were 85% (95% CI 72%-98%) and 51% (95% CI 31%-71%), respectively. Nivolumab administration significantly reduced PD-1 expression on all immune cells. CAR-T cell expansion was similar between nivolumab-eligible and noneligible patients. Notably, there was a significant enrichment of CD45RO-CD27+ CD8+ cells and CD45RO-CD27+ CD8+ CAR-T cells in the nivolumab-eligible group compared to those ineligible, suggesting that specific cell enrichment could potentially contribute to an enhanced response rate. We conclude that the addition of nivolumab based on CAR-T cell expansion in patients with SD/PD-LBCL is safe and yields promising early response rates. | [
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] | 2024-10-14 | 1 | 39396632 | [
"specific cell enrichment",
"Eligible patients",
"CAR-T cell expansion",
"CAR-T cells",
"Patients",
"patients",
"CD45RO-CD27+ CD8+ CAR-T cells",
"CD45RO-CD27+ CD8+ cells",
"early response rates",
"nivolumab",
"complete response",
"overall survival",
"large B-cell lymphoma",
"response",
"day",
"whose CAR-T cell levels",
"chimeric antigen receptor T cell (CAR-T) therapy",
"LBCL",
"all immune cells",
"day +5 and +9 post CAR-T infusion",
"peripheral blood",
"improved outcomes",
"anti-CD19 CAR-T (Axicabtagene ciloleucel",
"Nivolumab administration",
"an enhanced response rate",
"an 84% overall response rate",
"CI 36%-64%",
"active CAR-T-associated toxicities",
"nivolumab-eligible and noneligible patients",
"NCT05385263"
] | [
"CAR-T",
"Lymphoma",
"Nivolumab"
] | 0 | 10.1016/j.jtct.2024.09.024 | [
"Ram",
"Amit",
"Perry",
"Herishanu",
"Avivi",
"Sarid",
"Apel",
"Preis",
"Aviv",
"Shapira",
"Shragai",
"Joffe",
"Shargian",
"Herzog-Tsarfati",
"Eylati",
"Acria",
"Fridberg",
"Gold",
"Glait-Santar",
"Kay",
"Gal-Rabinovich",
"Rosenberg",
"Setter-Marco",
"Beyar-Katz"
] | [
"Tel Aviv Sourasky Medical Center, Hematology Institution, Tel Aviv, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: [email protected].",
"Tel Aviv Sourasky Medical Center, Hematology Institution, Tel Aviv, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.",
"Tel Aviv Sourasky Medical Center, Hematology Institution, Tel Aviv, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.",
"Tel Aviv Sourasky Medical Center, Hematology Institution, Tel Aviv, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.",
"Tel Aviv Sourasky Medical Center, Hematology Institution, Tel Aviv, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.",
"Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Hematology Department, Wolfson Medical Center, Holon, Israel.",
"Hematology Department, Shamir Medical Center, Be'er Ya'akov, Israel.",
"Hematology Department, Carmel Medical Center, Haifa, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.",
"Hematology Department, Emek Medical Center, Afula, Israel.",
"Hematology Department, Meir Medical Center, Kfar Saba, Israel.",
"Tel Aviv Sourasky Medical Center, Hematology Institution, Tel Aviv, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.",
"Tel Aviv Sourasky Medical Center, Hematology Institution, Tel Aviv, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.",
"Beilinson Medical Center, Hematology Institute, Petah Tikva, Israel.",
"Hematology Department, Shamir Medical Center, Be'er Ya'akov, Israel.",
"Tel Aviv Sourasky Medical Center, Hematology Institution, Tel Aviv, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.",
"Hematology and Blood bank, Galilee Medical Center, Nahariya, Israel.",
"Tel Aviv Sourasky Medical Center, Hematology Institution, Tel Aviv, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.",
"Tel Aviv Sourasky Medical Center, Hematology Institution, Tel Aviv, Israel.",
"Tel Aviv Sourasky Medical Center, Hematology Institution, Tel Aviv, Israel.",
"Tel Aviv Sourasky Medical Center, Hematology Institution, Tel Aviv, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.",
"Hematology laboratory, Rambam Health Care Campus, Haifa, Israel.",
"Hematology laboratory, Rambam Health Care Campus, Haifa, Israel.",
"Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel.",
"The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel; Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel."
] | [
"39396632"
] | [] | 6.247752 | 5.506422 |
39396256 | 383 | Allogeneic "Off-the-Shelf" CAR T cells: Challenges and advances. | Chimeric antigen receptor (CAR) T cell therapy has shown impressive clinical efficacy in B cell malignancies and multiple myeloma, leading to the approval of six CAR T cell products by the U.S. Food and Drug Administration (FDA) to date. However, broad application of these autologous (patient-derived) CAR T cells is limited by several factors, including high production costs, inconsistent product quality, contamination of the cell product with malignant cells, manufacturing failure especially in heavily pre-treated patients, and lengthy manufacturing times resulting in subsequent treatment delay. A potential solution to these barriers lies in the use of allogeneic "off-the-shelf" CAR T cells produced from healthy donors. Many efforts are underway to make allogeneic CAR T cells a safe and efficacious therapeutic option. In this review, we will discuss the major challenges that have to be addressed to successfully develop allogeneic CAR T cell therapies, specifically graft-versus-host disease (GVHD) and host-mediated immune rejection of the donor cells. Furthermore, we will summarize approaches that have been utilized to overcome these limitations, focusing on the use of gene editing technologies and strategies employing alternative cell populations as the source for allogeneic CAR T cell production. | [
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] | 2024-10-13 | 1 | 39396256 | [
"allogeneic CAR T cell therapies",
"allogeneic CAR T cell production",
"T cell therapy",
"allogeneic CAR T",
"malignant cells",
"alternative cell populations",
"B cell malignancies",
"six CAR T cell products",
"CAR",
"inconsistent product quality",
"high production costs",
"the cell product",
"impressive clinical efficacy",
"the donor cells",
"subsequent treatment delay",
"several factors",
"multiple myeloma",
"Chimeric antigen receptor",
"these autologous (patient-derived) CAR T cells",
"healthy donors",
"host",
"heavily pre-treated patients",
"broad application",
"Many efforts",
"host-mediated immune rejection",
"technologies",
"strategies",
"failure",
"approaches",
"GVHD"
] | [
"Allogeneic",
"Chimeric antigen receptor T cells",
"Gene editing",
"Graft-versus-host disease",
"Immune rejection",
"Off-the-shelf"
] | 0 | 10.1016/j.beha.2024.101566 | [
"Chen",
"van den Brink"
] | [
"Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, 417 E 68th St, New York, NY, 10065, USA; City of Hope National Medical Center, 1500 E Duarte Rd, Duarte, CA, 91010, USA. Electronic address: [email protected].",
"City of Hope National Medical Center, 1500 E Duarte Rd, Duarte, CA, 91010, USA. Electronic address: [email protected]."
] | [
"39396256"
] | [] | 8.25836 | 3.297443 |
39387839 | 384 | Targeting Tumor Antigen 5T4 Using CAR T Cells for the Treatment of Acute Myeloid Leukemia. | Chimeric antigen receptor (CAR) T cells represent a novel targeted approach to overcome deficits in the ability of the host immune system to detect and subsequently eradicate tumors. The identification of antigens expressed specifically on the surface of tumor cells is a critical first step for a targeted therapy that selectively targets cancer cells without affecting normal tissues. 5T4 is a tumor-associated antigen expressed on the cell surface of most solid tumors. However, very little is known about its expression in hematologic malignancies. In this study, we assess the expression of 5T4 in different types of leukemias, specifically acute myeloid leukemia (AML), and normal hematopoietic stem cells (HSC). We also provide an in vitro assessment of safety and efficacy of 5T4-targeting CAR T cells against HSCs and AML tumor cell lines. 5T4 expression was seen in about 50% of AML cases; AML with mutated nucleophosmin 1, AML-myelodysplasia-related, and AML not otherwise specified showed the highest percentage of 5T4+ cases. 5T4 CAR T cells efficiently and specifically killed AML tumor cell lines, including leukemic stem cells. Coculture of 5T4 CAR T cells with HSCs from healthy donors showed no impact on subsequent colony formation, thus confirming the safety profile of 5T4. A proof-of-concept study using a murine model for AML demonstrated that CAR T cells recognize 5T4 expressed on cells and can kill tumor cells both in vitro and in vivo. These results highlight 5T4 as a promising target for immune intervention in AML and that CAR T cells can be considered a powerful personalized therapeutic approach to treat AML. | [
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] | 2024-10-13 | 1 | 39387839 | [
"AML tumor cell lines",
"CAR T cells",
"tumor cells",
"cells",
"cancer cells",
"normal hematopoietic stem cells",
"leukemic stem cells",
"AML cases",
"AML",
"5T4 CAR T cells",
"that CAR T cells",
"most solid tumors",
"tumors",
"CAR",
"immune intervention",
"subsequent colony formation",
"the cell surface",
"5T4-targeting CAR T cells",
"different types",
"normal tissues",
"healthy donors",
"antigens",
"safety",
"hematologic malignancies",
"mutated nucleophosmin",
"leukemias",
"a novel targeted approach",
"HSCs",
"a powerful personalized therapeutic approach",
"AML-myelodysplasia-related"
] | [] | 0 | 10.1158/1535-7163.MCT-24-0052 | [
"Harrop",
"Blount",
"Khan",
"Soyombo",
"Moyce",
"Drayson",
"Down",
"Lawson",
"O'Connor",
"Nimmo",
"Lad",
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] | [
"Oxford Biomedica (UK) Limited, Oxford, United Kingdom.",
"Oxford Biomedica (UK) Limited, Oxford, United Kingdom.",
"Clinical Immunology Service, University of Birmingham, Birmingham, United Kingdom.",
"Oxford Biomedica (UK) Limited, Oxford, United Kingdom.",
"Oxford Biomedica (UK) Limited, Oxford, United Kingdom.",
"Clinical Immunology Service, University of Birmingham, Birmingham, United Kingdom.",
"Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, United Kingdom.",
"Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, United Kingdom.",
"Oxford Biomedica (UK) Limited, Oxford, United Kingdom.",
"Oxford Biomedica (UK) Limited, Oxford, United Kingdom.",
"Oxford Biomedica (UK) Limited, Oxford, United Kingdom.",
"Oxford Biomedica (UK) Limited, Oxford, United Kingdom.",
"Oxford Biomedica (UK) Limited, Oxford, United Kingdom.",
"Oxford Biomedica (UK) Limited, Oxford, United Kingdom."
] | [
"39387839"
] | [] | 7.076122 | 6.904348 |
39393068 | 385 | T-cell lymphomas in recipients of CAR-T cells: assessing risks and causalities. | The US Food and Drug Administration announcement in November 2023 regarding reports of the occurrence of secondary T-cell lymphomas in patients receiving chimeric antigen receptor T cells (CAR-Ts) for B-cell malignancies resulted in widespread concern among patients, clinicians, and scientists. Little information relevant to assessing causality, most importantly whether CAR retroviral or lentiviral vector genomic insertions contribute to oncogenesis, was initially available. However, since that time, several publications have provided clinical and molecular details on 3 cases showing clonal CAR vector insertions in tumor cells but without firm evidence these insertions played any role in oncogenic transformation. In addition, several other cases have been reported without vector detected in tumor cells. In addition, epidemiologic analyses as well as institutional long-term CAR-T recipient cohort studies provide important additional information suggesting the risk of T-cell lymphomas after CAR-T therapies is extremely low. This review will provide a summary of information available to date, as well as review relevant prior research suggesting a low susceptibility of mature T cells to insertional oncogenesis and documenting the almost complete lack of T-cell transformation after natural HIV infection. Alternative factors that may predispose patients treated with CAR-Ts to secondary hematologic malignancies, including immune dysfunction and clonal hematopoiesis, are discussed, and likely play a greater role than insertional mutagenesis in secondary malignancies after CAR therapies. | [
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] | 2024-10-11 | 1 | 39393068 | [
"mature T cells",
"chimeric antigen receptor T cells",
"clonal CAR vector insertions",
"tumor cells",
"CAR therapies",
"secondary hematologic malignancies",
"secondary malignancies",
"lentiviral vector genomic insertions",
"CAR",
"secondary T-cell lymphomas",
"important additional information",
"several other cases",
"T-cell transformation",
"CAR retroviral or lentiviral vector genomic insertions",
"T-cell lymphomas",
"insertional oncogenesis",
"relevant prior research",
"patients",
"vector",
"Little information",
"clonal hematopoiesis",
"insertional mutagenesis",
"B-cell malignancies",
"information",
"institutional long-term CAR-T recipient cohort studies",
"several publications",
"oncogenic transformation",
"widespread concern",
"immune dysfunction",
"natural HIV infection"
] | [] | 0 | 10.1182/blood.2024025828 | [
"Hu",
"Dunbar"
] | [
"Department of Cell Therapy, Stem Cell Center, Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.",
"Division of Intramural Research, Translational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD."
] | [
"39393068"
] | [] | 6.699729 | 4.488995 |
39389969 | 386 | To tackle the clinical challenge of noninvasively assessing immunotherapy efficacy in patients, here we used positron emission tomography (PET) with | [
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] | 2024-10-11 | 46 | 39389969 | [
"positron emission tomography",
"immunotherapy efficacy",
"patients",
"PET",
"the clinical challenge",
"we"
] | [] | 0 | 10.1038/s41467-024-53197-2 | [
"Shen",
"Zhou",
"Zhou",
"Liu",
"Meng",
"Zhang",
"Song",
"Guo",
"Wang",
"Li",
"Li",
"Yang",
"Liu",
"Li"
] | [
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, 100142, Beijing, China.\nKey Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Peking University Cancer Hospital & Institute, 100142, Beijing, China.",
"State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, 100191, Beijing, China.",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, 100142, Beijing, China.\nKey Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Peking University Cancer Hospital & Institute, 100142, Beijing, China.",
"State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, 100142, Beijing, China.",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, 100142, Beijing, China.\nKey Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Peking University Cancer Hospital & Institute, 100142, Beijing, China.",
"State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, 100191, Beijing, China.",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, 100142, Beijing, China.\nKey Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Peking University Cancer Hospital & Institute, 100142, Beijing, China.",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, 100142, Beijing, China.\nKey Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Peking University Cancer Hospital & Institute, 100142, Beijing, China.",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, 100142, Beijing, China.\nKey Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Peking University Cancer Hospital & Institute, 100142, Beijing, China.",
"State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, 100191, Beijing, China.",
"State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, 100142, Beijing, China.",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, 100142, Beijing, China. [email protected].\nKey Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Peking University Cancer Hospital & Institute, 100142, Beijing, China. [email protected].",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, 100142, Beijing, China. [email protected].\nKey Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Peking University Cancer Hospital & Institute, 100142, Beijing, China. [email protected].\nState Key Laboratory of Vascular Homeostasis and Remodeling, Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, 100191, Beijing, China. [email protected].\nDepartment of Nuclear Medicine, Peking University Third Hospital, 100191, Beijing, China. [email protected].",
"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, 100142, Beijing, China. [email protected].\nKey Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Peking University Cancer Hospital & Institute, 100142, Beijing, China. [email protected]."
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|
39386600 | 387 | AMPK agonism optimizes the | Chimeric antigen receptor T cell (CART) therapy has seen great clinical success. However, up to 50% of leukemia patients relapse and long-term survivor data indicate that CART cell persistence is key to enforcing relapse-free survival. Unfortunately, ex vivo expansion protocols often drive metabolic and functional exhaustion, reducing in vivo efficacy. Preclinical models have demonstrated that redirecting metabolism ex vivo can improve in vivo T cell function and we hypothesized that exposure to an agonist targeting the metabolic regulator AMP-activated protein kinase (AMPK), would create CARTs capable of both efficient leukemia clearance and increased in vivo persistence.
CART cells were generated from healthy human via lentiviral transduction. Following activation, cells were exposed to either Compound 991 or DMSO for 96 hours, followed by a 48-hour washout. During and after agonist treatment, T cells were harvested for metabolic and functional assessments. To test in vivo efficacy, immunodeficient mice were injected with luciferase+ NALM6 leukemia cells, followed one week later by either 991- or DMSO-expanded CARTs. Leukemia burden and anti-leukemia efficacy was assessed via radiance imaging and overall survival.
Human T cells expanded in Compound 991 activated AMPK without limiting cellular expansion and gained both mitochondrial density and improved handling of reactive oxygen species (ROS). Importantly, receipt of 991-exposed CARTs significantly improved in vivo leukemia clearance, prolonged recipient survival, and increased CD4+ T cell yields at early times post-injection. Ex vivo, 991 agonist treatment mimicked nutrient starvation, increased autophagic flux, and promoted generation of mitochondrially-protective metabolites.
Ex vivo expansion processes are necessary to generate sufficient cell numbers, but often promote sustained activation and differentiation, negatively impacting in vivo persistence and function. Here, we demonstrate that promoting AMPK activity during CART expansion metabolically reprograms cells without limiting T cell yield, enhances in vivo anti-leukemia efficacy, and improves CD4+ in vivo persistence. Importantly, AMPK agonism achieves these results without further modifying the expansion media, changing the CART construct, or genetically altering the cells. Altogether, these data highlight AMPK agonism as a potent and readily translatable approach to improve the metabolic profile and overall efficacy of cancer-targeting T cells. | [
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"vivo T cell function",
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"cancer-targeting T cells",
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] | [
"AMP-activated protein kinase (AMPK)",
"Adoptive Cellular Therapies",
"Autophagy",
"Fatty Acid Oxidation",
"Immunometabolism",
"In vivo persistence"
] | 0 | 10.1101/2024.09.26.615290 | [
"Braverman",
"Qin",
"Schuler",
"Brown",
"Wittmann",
"Ramgopal",
"Kemp",
"Mullet",
"Yang",
"Poholek",
"Gelhaus",
"Byersdorfer"
] | [
"Department of Pediatrics, Division of Blood and Marrow Transplant and Cellular Therapies, University of Pittsburgh School of Medicine, Pittsburgh PA 15224.",
"Department of Pediatrics, Division of Blood and Marrow Transplant and Cellular Therapies, University of Pittsburgh School of Medicine, Pittsburgh PA 15224.\nSchool of Medicine, Tsinghua University, Beijing, China.",
"Department of Pediatrics, Division of Blood and Marrow Transplant and Cellular Therapies, University of Pittsburgh School of Medicine, Pittsburgh PA 15224.",
"Department of Pediatrics, Division of Blood and Marrow Transplant and Cellular Therapies, University of Pittsburgh School of Medicine, Pittsburgh PA 15224.",
"Department of Pediatrics, Division of Blood and Marrow Transplant and Cellular Therapies, University of Pittsburgh School of Medicine, Pittsburgh PA 15224.",
"Department of Pediatrics, Division of Blood and Marrow Transplant and Cellular Therapies, University of Pittsburgh School of Medicine, Pittsburgh PA 15224.",
"Department of Pediatrics, Division of Blood and Marrow Transplant and Cellular Therapies, University of Pittsburgh School of Medicine, Pittsburgh PA 15224.",
"Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA, USA.",
"Department of Pediatrics, Division of Pediatric Rheumatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.",
"Department of Pediatrics, Division of Pediatric Rheumatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.",
"Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA, USA.",
"Department of Pediatrics, Division of Blood and Marrow Transplant and Cellular Therapies, University of Pittsburgh School of Medicine, Pittsburgh PA 15224."
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39386214 | 388 | Case report: sub-clinical extramedullary B-ALL in the setting of relapse following targeted therapy. | Standard testing for disease evaluation in B-cell acute lymphoblastic leukemia (B-ALL) includes examination of the bone marrow and cerebrospinal fluid. Radiographic or functional imaging are indicated when clinical signs of non-CNS extramedullary disease are present but are not standard in the relapsed/refractory setting. We describe two cases of patients with relapsed/refractory B-ALL with prior exposure to blinatumomab and/or inotuzumab ozogamicin presenting for CAR-T cell treatment. Both patients were thought to only have minimal residual disease (MRD) at the pre-CAR disease assessment, with MRD of 6,648 (0.66%) and 100 (0.01%) cells per million cells, respectively, as measured by next-generation sequencing (NGS) in their bone marrows. Both patients for distinct reasons unrelated to non-CNS extra-medullary (EM) symptoms had PET-MRIs prior to lymphodepletion and CAR T cell infusion. In both cases patients were found to have significant bulky subclinical EM disease that required changes in clinical management. In the newly-emergent era of antigen-targeted immunotherapy, it is foundational that incidence and relapse patterns following targeted therapy are well-understood. Herein we contribute to a growing body of literature addressing this fundamental clinical gap and highlight a future role for formal prospective imaging studies to better establish response, toxicity and relapse patterns following CAR-T cell therapy in EM B-ALL. | [
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10.1016/j.ejrad.2015.11.019
10.1002/ajh.24287
10.1182/bloodadvances.2023010461
10.3390/cells11243991
10.1182/bloodadvances.2020001450
10.1200/JCO.20.03585 | [
"Johns",
"Erickson",
"Jacobs",
"Moon",
"Baggott",
"Dagher",
"Nadel",
"Balagtas",
"Aftandilian",
"Ramakrishna",
"Lacayo",
"Davis",
"Stieglitz",
"Schultz"
] | [
"Division of Pediatric Hematology/Oncology/Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford Medicine, Stanford, San Francisco, CA, United States.",
"Division of Pediatric Hematology/Oncology/Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford Medicine, Stanford, San Francisco, CA, United States.",
"Division of Pediatric Hematology/Oncology/Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford Medicine, Stanford, San Francisco, CA, United States.",
"Division of Pediatric Hematology/Oncology/Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford Medicine, Stanford, San Francisco, CA, United States.",
"Division of Pediatric Hematology/Oncology/Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford Medicine, Stanford, San Francisco, CA, United States.",
"Division of Pediatric Hematology/Oncology/Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford Medicine, Stanford, San Francisco, CA, United States.",
"Division of Pediatric Hematology/Oncology/Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford Medicine, Stanford, San Francisco, CA, United States.",
"Division of Pediatric Hematology/Oncology/Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford Medicine, Stanford, San Francisco, CA, United States.",
"Division of Pediatric Hematology/Oncology/Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford Medicine, Stanford, San Francisco, CA, United States.",
"Division of Pediatric Hematology/Oncology/Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford Medicine, Stanford, San Francisco, CA, United States.",
"Division of Pediatric Hematology/Oncology/Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford Medicine, Stanford, San Francisco, CA, United States.",
"Division of Pediatric Hematology/Oncology/Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford Medicine, Stanford, San Francisco, CA, United States.",
"Division of Pediatric Oncology, Department of Pediatrics, University of California San Francisco School of Medicine, San Francisco State, San Francisco, CA, United States.",
"Division of Pediatric Hematology/Oncology/Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford Medicine, Stanford, San Francisco, CA, United States."
] | [
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] | [] | 6.492099 | 6.424894 |
39386211 | 389 | Automated manufacturing and characterization of clinical grade autologous CD20 CAR T cells for the treatment of patients with stage III/IV melanoma. | Point-of-care (POC) manufacturing of chimeric antigen receptor (CAR) modified T cell has expanded rapidly over the last decade. In addition to the use of CD19 CAR T cells for hematological diseases, there is a growing interest in targeting a variety of tumor-associated epitopes.
Here, we report the manufacturing and characterization of autologous anti-CD20 CAR T cells from melanoma patients within phase I clinical trial (NCT03893019). Using a second-generation lentiviral vector for the production of the CD20 CAR T cells on the CliniMACS Prodigy®.
We demonstrated consistency in cell composition and functionality of the products manufactured at two different production sites. The T cell purity was >98.5%, a CD4/CD8 ratio between 2.5 and 5.5 and transduction rate between 34% and 61% on day 12 (harvest). Median expansion rate was 53-fold (range, 42-65-fold) with 1.7-3.8×10
In conclusion, the CliniMACS Prodigy® platform is well suited for decentralized POC manufacturing of anti-CD20 CAR T cells and may be likewise applicable for the rapid and automated manufacturing of CAR T cells directed against other targets.
https://clinicaltrials.gov/study/NCT03893019?cond=Melanoma&term=NCT03893019&rank=1, identifier NCT03893019. | [
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] | 2024-10-10 | 39 | 39386211 | [
"CAR T cells",
"anti-CD20 CAR T cells",
"CD19 CAR T cells",
"autologous anti-CD20 CAR T cells",
"cell composition",
"decentralized POC manufacturing",
"the CD20 CAR T cells",
"The T cell purity",
"CAR",
"Median expansion rate",
"chimeric antigen receptor",
"melanoma patients",
"hematological diseases",
"identifier NCT03893019",
"the CliniMACS Prodigy® platform",
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"53-fold",
"conclusion",
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"two different production sites",
"characterization",
"consistency",
"day",
"tumor-associated epitopes",
"care"
] | [
"CD20 CAR investigational medicinal product",
"automated manufacturing of engineered T cell products",
"cell composition of CAR T cell products",
"clinical CD20 CAR T cell trial",
"ex vivo expansion"
] | 0 | 10.3389/fimmu.2024.1328368
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10.1038/s41591-022-02017-5
10.1016/S0140-6736(23)00023-5 | [
"Aleksandrova",
"Leise",
"Priesner",
"Aktas",
"Apel",
"Assenmacher",
"Bürger",
"Richter",
"Altefrohne",
"Schubert",
"Holzinger",
"Barden",
"Bezler",
"von Bergwelt-Baildon",
"Borchmann",
"Goudeva",
"Glienke",
"Arseniev",
"Esser",
"Abken",
"Koehl"
] | [
"Institute of Cellular Therapeutics (ICT), Hannover Medical School (MHH), Hanover, Germany.",
"Institute of Cellular Therapeutics (ICT), Hannover Medical School (MHH), Hanover, Germany.",
"Institute of Cellular Therapeutics (ICT), Hannover Medical School (MHH), Hanover, Germany.",
"Miltenyi Biotec B.V. & Co. KG, Bergisch Gladbach, Germany.",
"Miltenyi Biotec B.V. & Co. KG, Bergisch Gladbach, Germany.",
"Miltenyi Biotec B.V. & Co. KG, Bergisch Gladbach, Germany.",
"Miltenyi Biotec B.V. & Co. KG, Bergisch Gladbach, Germany.",
"Miltenyi Biotec B.V. & Co. KG, Bergisch Gladbach, Germany.",
"Miltenyi Biomedicine GmbH, Bergisch Gladbach, Germany.",
"Miltenyi Biomedicine GmbH, Bergisch Gladbach, Germany.",
"Division of Genetic Immunotherapy, Leibniz Institute for Immunotherapy (LIT) and University of Regensburg, Regensburg, Germany.",
"Division of Genetic Immunotherapy, Leibniz Institute for Immunotherapy (LIT) and University of Regensburg, Regensburg, Germany.",
"Division of Genetic Immunotherapy, Leibniz Institute for Immunotherapy (LIT) and University of Regensburg, Regensburg, Germany.",
"Medical Department III, Hospital of the Ludwig Maximillian University of Munich (LMU), Munich, Germany.",
"Internal Medicine, University Hospital Cologne, Cologne, Germany.",
"Institute of Transfusion Medicine and Transplant Engineering (ITMTE), Hannover Medical School, Hannover, Germany.",
"Institute of Cellular Therapeutics (ICT), Hannover Medical School (MHH), Hanover, Germany.",
"Institute of Cellular Therapeutics (ICT), Hannover Medical School (MHH), Hanover, Germany.",
"Institute of Cellular Therapeutics (ICT), Hannover Medical School (MHH), Hanover, Germany.",
"Division of Genetic Immunotherapy, Leibniz Institute for Immunotherapy (LIT) and University of Regensburg, Regensburg, Germany.",
"Institute of Cellular Therapeutics (ICT), Hannover Medical School (MHH), Hanover, Germany.\nFraunhofer Institute for Cell Therapy and Immunology (IZI), Leipzig, Germany.\nInstitute of Clinical Immunology, University of Leipzig, Leipzig, Germany."
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] | [] | 8.571243 | 3.080067 |
39383607 | 390 | Homology-independent targeted insertion-mediated derivation of M1-biased macrophages harbouring Megf10 and CD3ζ from human pluripotent stem cells. | Macrophages engineered with chimeric antigen receptors (CAR) are suitable for immunotherapy based on their immunomodulatory activity and ability to infiltrate solid tumours. However, the production and application of genetically edited, highly effective, and mass-produced CAR-modified macrophages (CAR-Ms) are challenging.
Here, we used homology-independent targeted insertion (HITI) for site-directed CAR integration into the safe-harbour region of human pluripotent stem cells (hPSCs). This approach, together with a simple differentiation protocol, produced stable and highly effective CAR-Ms without heterogeneity.
These engineered cells phagocytosed cancer cells, leading to significant inhibition of cancer-cell proliferation in vitro and in vivo. Furthermore, the engineered CARs, which incorporated a combination of CD3ζ and Megf10 (referred to as FRP5
Our findings suggest that CAR-Ms have promise as immunotherapeutics. In conclusion, the guided insertion of CAR containing CD3ζ and Megf10 domains is an effective strategy for the immunotherapy of solid tumours.
This work was supported by KRIBB Research Initiative Program Grant (KGM4562431, KGM5282423) and a Korean Fund for Regenerative Medicine (KFRM) grant funded by the Korean government (Ministry of Science and ICT,Ministry of Health and Welfare) (22A0304L1-01). | [
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] | 0 | 10.1016/j.ebiom.2024.105390 | [
"Zhen",
"Kim",
"Kang",
"Choi",
"Park",
"Lee",
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] | [
"National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, 28116, Republic of Korea; Department of Nanoscience and Nanotechnology, Graduate School, Kyungpook National University, Daegu, 41566, Republic of Korea. Electronic address: [email protected].",
"National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, 28116, Republic of Korea; Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea; Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea. Electronic address: [email protected].",
"Laboratory Animal Resource and Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, 28116, Republic of Korea. Electronic address: [email protected].",
"Laboratory Animal Resource and Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, 28116, Republic of Korea. Electronic address: [email protected].",
"Laboratory Animal Resource and Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, 28116, Republic of Korea. Electronic address: [email protected].",
"Department of Nanoscience and Nanotechnology, Graduate School, Kyungpook National University, Daegu, 41566, Republic of Korea; School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu, 41566, Republic of Korea. Electronic address: [email protected].",
"Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon, 24341, Republic of Korea; KW-Bio Co., Ltd, Chuncheon, 24252, South Korea. Electronic address: [email protected].",
"National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, 28116, Republic of Korea; Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology (UST), Daejeon, 34113, Republic of Korea. Electronic address: [email protected]."
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39382681 | 391 | Exploring miRNA therapies and gut microbiome-enhanced CAR-T cells: advancing frontiers in glioblastoma stem cell targeting. | Glioblastoma multiforme (GBM) presents a formidable challenge in oncology due to its aggressive nature and resistance to conventional treatments. Recent advancements propose a novel therapeutic strategy combining microRNA-based therapies, chimeric antigen receptor-T (CAR-T) cells, and gut microbiome modulation to target GBM stem cells and transform cancer treatment. MicroRNA therapies show promise in regulating key signalling pathways implicated in GBM progression, offering the potential to disrupt GBM stem cell renewal. CAR-T cell therapy, initially successful in blood cancers, is being adapted to target GBM by genetically engineering T cells to recognise and eliminate GBM stem cell-specific antigens. Despite early successes, challenges like the immunosuppressive tumour microenvironment persist. Additionally, recent research has uncovered a link between the gut microbiome and GBM, suggesting that gut dysbiosis can influence systemic inflammation and immune responses. Novel strategies to modulate the gut microbiome are emerging, enhancing the efficacy of microRNA therapies and CAR-T cell treatments. This combined approach highlights the synergistic potential of these innovative therapies in GBM treatment, aiming to eradicate primary tumours and prevent recurrence, thereby improving patient prognosis and quality of life. Ongoing research and clinical trials are crucial to fully exploit this promising frontier in GBM therapy, offering hope to patients grappling with this devastating disease. | [
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] | 0 | 10.1007/s00210-024-03479-9
10.1016/j.jncc.2023.08.001
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10.1016/j.critrevonc.2021.103283 | [
"Sandhanam",
"Tamilanban",
"Bhattacharjee",
"Manasa"
] | [
"Department of Pharmacology, SRM College of Pharmacy, SRM Institute of Science and Technology, Chengalpattu, 603203, Tamil Nadu, India.",
"Department of Pharmacology, SRM College of Pharmacy, SRM Institute of Science and Technology, Chengalpattu, 603203, Tamil Nadu, India. [email protected].",
"Department of Pharmacology, Girijananda Chowdhury University-Tezpur Campus, 784501, Assam, India.",
"Department of Pharmacology, MNR College of Pharmacy, Sangareddy, 502294, Telangana, India."
] | [
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39379249 | 392 | The winding road: Infectious disease considerations for CAR-T and other novel adoptive cellular therapies in the era of COVID-19. | Adoptive cellular therapies (ACT) are novel, promising treatments for life-threatening malignancies. In addition to the better known chimeric antigen receptor (CAR) T cells, ACTs include tumor infiltrating lymphocytes (TIL), cancer antigen-specific T cell receptors (TCRs), and CAR-NK (natural killer) cells. In key historic milestones, several adoptive therapies recently received FDA approvals, including 6 CAR-T products for the treatment of hematologic malignancies and the first TIL therapy for the treatment for metastatic melanoma. The rapid pace of clinical trials in the field and the discoveries they provide are ushering in a new era of cancer immunotherapy. However, the potential complications of these therapies are still not fully understood. In particular, patients receiving ACT may be at increased risk for severe infections due to immunocompromise resulting from their underlying malignancies, which are further compounded by the immune derangements that develop in the setting of cellular immunotherapy and/or the preconditioning treatment needed to enhance ACT efficacy. Moreover, these treatments are being readily implemented at a time following the height of the COVID-19 pandemic, and it remains unclear what additional risks these patients may face from SARS-CoV-2 and similar infections. Here, we examine the evidence for infectious complications with emerging adoptive therapies, and provide a focused review of the epidemiology, complications, and clinical management for COVID-19 in CAR-T recipients to understand the risk this disease may pose to recipients of other forms of ACT. | [
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] | 2024-10-09 | 142 | 39379249 | [
"Adoptive cellular therapies",
"several adoptive therapies",
"emerging adoptive therapies",
"treatments",
"increased risk",
"ACT efficacy",
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] | [
"Adoptive cellular therapy",
"CAR-T",
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"Infections",
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] | 0 | 10.1053/j.seminhematol.2024.08.002 | [
"Singh",
"Rocco",
"Nussenblatt"
] | [
"Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD. Electronic address: [email protected].",
"Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.",
"Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD."
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39379118 | 393 | CAR T-cell therapy in acute myeloid leukemia. | Acute myeloid leukemia (AML) is an aggressive leukemic malignancy that affects myeloid lineage progenitors. Relapsed or refractory AML patients continue to have poor prognoses, necessitating the development of novel therapy alternatives. Adoptive T-cell therapy with chimeric antigen receptors (CARs) is an intriguing possibility in the field of leukemia treatment. Chimeric antigen receptor T-cell therapy is now being tested in clinical trials (mostly in phase I and phase II) using AML targets including CD33, CD123, and CLL-1. Preliminary data showed promising results. However, due to the cellular and molecular heterogeneity of AML and the co-expression of some AML targets on hematopoietic stem cells, these clinical investigations have shown substantial "on-target off-tumor" toxicities, indicating that more research is required. In this review, the latest significant breakthroughs in AML CAR T cell therapy are presented. Furthermore, the limitations of CAR T-cell technology and future directions to overcome these challenges are discussed. | [
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] | [
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"adoptive T-cell therapy",
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] | 0 | 10.15537/smj.2024.45.10.20240330
10.1007/978-3-030-72676-8 | [
"Almotiri"
] | [
"From the Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Shaqra University, Shaqra, Kingdom of Saudi Arabia."
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39378897 | 394 | A microphysiological assay for studying T-cell chemotaxis, trafficking and tumor killing. | Tumors in patients non-responsive to immunotherapy harbor a series of barriers that impede the efficacy of effector T-cells. Consequently, therapeutically modulating the chemotaxis machinery to enable effector T cell infiltration and function in the tumor could result in more successful therapeutic outcomes. Complex | [
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] | 0 | 10.1088/1758-5090/ad847f | [
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"Complex In-Vitro Models, GSK, Collegeville, PA, United States of America.",
"Genome Biology, GSK, Collegeville, PA, United States of America.",
"Genome Biology, GSK, Collegeville, PA, United States of America.",
"Genome Biology, GSK, Collegeville, PA, United States of America.",
"Research Statistics, GSK, Collegeville, PA, United States of America.",
"Complex In-Vitro Models, GSK, Collegeville, PA, United States of America.",
"Complex In-Vitro Models, GSK, Collegeville, PA, United States of America.",
"Chemical Biology, GSK, Collegeville, PA, United States of America.",
"Immuno-Oncology and Combinations (IOC), GSK, Collegeville, PA, United States of America.",
"Oncology Cell Therapy, GSK, Stevenage, United Kingdom.",
"Oncology Cell Therapy, GSK, Stevenage, United Kingdom.",
"Oncology Translational Research, GSK, Stevenage, United Kingdom.",
"Genome Biology, GSK, Collegeville, PA, United States of America.",
"Complex In-Vitro Models, GSK, Collegeville, PA, United States of America."
] | [
"39378897"
] | [] | 10.298346 | 4.936337 |
39378059 | 395 | Allogeneic CAR-T cells for cancer immunotherapy. | Autologous chimeric antigen receptor (CAR)-modified T (CAR-T) cell therapy has displayed high efficacy in the treatment of hematological malignancies. Up to now, 11 autologous CAR-T cell products have been approved for the management of malignancies globally. However, the application of autologous CAR-T cell therapy has many individual limitations, long time-consuming, highly cost, and the risk of manufacturing failure. Indeed, some patients would not benefit from autologous CAR-T cell products because of rapid disease progression. Allogeneic CAR-T cells especially universal CAR-T (U-CAR-T) cell therapy are superior to these challenges of autologous CAR-T cells. In this review, we describe basic study and clinical trials of U-CAR-T cell therapeutic methods for malignancies. In addition, we summarize the problems encountered and potential solutions.
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10.3389/fonc.2022.809754 | [
"Chen",
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"Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.\nCancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.",
"Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.",
"Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.\nCancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.\nState Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou, Henan, 450052, China.\nSchool of Life Sciences, Zhengzhou University, Zhengzhou, Henan, 450052, China.\nTianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450052, China."
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39377542 | 396 | Unlocking Apoptotic Pathways: Overcoming Tumor Resistance in CAR-T-Cell Therapy. | Chimeric antigen receptor (CAR)-T-cell therapy has transformed cancer treatment, leading to remarkable clinical outcomes. However, resistance continues to be a major obstacle, significantly limiting its efficacy in numerous patients.
This review critically examines the challenges associated with CAR-T-cell therapy, with a particular focus on the role of apoptotic pathways in overcoming resistance.
We explore various strategies to sensitize tumor cells to CAR-T-cell-mediated apoptosis, including the use of combination therapies with BH3 mimetics, Mcl-1 inhibitors, IAP inhibitors, and HDAC inhibitors. These agents inhibit anti-apoptotic proteins and activate intrinsic mitochondrial pathways, enhancing the susceptibility of tumor cells to apoptosis. Moreover, targeting the extrinsic pathway can increase the expression of death receptors on tumor cells, further promoting their apoptosis. The review also discusses the development of novel CAR constructs that enhance anti-apoptotic protein expression, such as Bcl-2, which may counteract CAR-T cell exhaustion and improve antitumor efficacy. We assess the impact of the tumor microenvironment (TME) on CAR-T cell function and propose dual-targeting CAR-T cells to simultaneously address both myeloid-derived suppressor cells (MDSCs) and tumor cells. Furthermore, we explore the potential of combining agents like PPAR inhibitors to activate the cGAS-STING pathway, thereby improving CAR-T cell infiltration into the tumor.
This review highlights that enhancing tumor cell sensitivity to apoptosis and increasing CAR-T cell cytotoxicity through apoptotic pathways could significantly improve therapeutic outcomes. Targeting apoptotic proteins, particularly those involved in the intrinsic mitochondrial pathway, constitutes a novel approach to overcoming resistance. The insights presented herein lay a robust foundation for future research and clinical applications aimed at optimizing CAR-T cell therapies. | [
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] | 2024-10-08 | 93 | 39377542 | [
"tumor cells",
"tumor cell sensitivity",
"apoptotic pathways",
"anti-apoptotic protein expression",
"anti-apoptotic proteins",
"intrinsic mitochondrial pathways",
"apoptotic proteins",
"CAR-T cell therapies",
"novel CAR",
"CAR-T cell exhaustion",
"CAR-T cell function",
"CAR-T cell cytotoxicity",
"CAR-T cell infiltration",
"CAR",
"combination therapies",
"PPAR inhibitors",
"Mcl-1 inhibitors",
"CAR)-T-cell therapy",
"IAP inhibitors",
"remarkable clinical outcomes",
"HDAC inhibitors",
"apoptosis",
"CAR-T-cell therapy",
"Chimeric antigen receptor",
"death receptors",
"antitumor efficacy",
"the intrinsic mitochondrial pathway",
"cancer treatment",
"BH3 mimetics",
"CAR-T-cell-mediated apoptosis"
] | [
"CAR‐T‐cell therapy resistance",
"apoptotic pathways",
"tumor",
"tumor microenvironment"
] | 0 | 10.1002/cam4.70283 | [
"Zhang",
"Su",
"Jiang",
"Wang",
"Tong",
"Wu"
] | [
"Department of Hematology, Dongyang Hospital Affiliated to WenZhou Medical University, Jinhua, Zhejiang, China.",
"Department of Hematology, Dongyang Hospital Affiliated to WenZhou Medical University, Jinhua, Zhejiang, China.",
"Department of Hematology, Dongyang Hospital Affiliated to WenZhou Medical University, Jinhua, Zhejiang, China.",
"Department of Hematology, Dongyang Hospital Affiliated to WenZhou Medical University, Jinhua, Zhejiang, China.",
"Department of Central Laboratory, School of Medicine, Affiliated Hangzhou First People's Hospital, WestLake University, Zhejiang, Hangzhou, China.",
"Department of Hematology, Dongyang Hospital Affiliated to WenZhou Medical University, Jinhua, Zhejiang, China."
] | [
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39376984 | 397 | How to optimize the CAR-T Cell therapy process? A group concept mapping analysis of preconditions for a frictionless process from a German multistakeholder perspective. | Treatment with chimeric antigen receptor T (CAR-T) cells involves a large number of interdisciplinary stakeholders and is associated with complex processes ranging from patient-specific production to follow-up care. Due to the complexity, maximum process optimization is required in order to avoid efficiency losses. This study aimed at systematically determining the preconditions for a frictionless flow of the CAR-T process by surveying the stakeholders involved.
A Group Concept Mapping (GCM) analysis, a mixed-methods participatory research, was conducted. CAR-T experts from different professional backgrounds went through three steps: 1) Brainstorming relevant aspects (statements) for a frictionless process, 2) Sorting the collected statements based on their similarity, and 3) Rating the importance and feasibility of each statement. A cluster map reflecting the overarching topics was derived, and mean ratings per statement and cluster were calculated.
Overall, 20 CAR-T experts participated. A total of 80 statements were collected, resulting in a map of the following 10 clusters (mean importance/feasibility): Information for patients and physicians (4.16/3.77), Supportive network (4.03/3.53), Eligibility of patients (4.41/3.63), Evidence, transparency and communication (4.01/3.33), Paperwork (4.1/2.52), Interface with pharmaceutical manufacturer (4.03/2.85), Reimbursement (4.29/2.31), Quality Management (4.17/3.18), Infrastructure of CAR-T clinics (4.1/2.93), and Patient-oriented processes (4.46/3.32).
The 80 statements underlined the complex and manifold nature of the CAR-T treatment process. Our results reflect the first step in overcoming hurdles: identifying potential hurdles and required preconditions. Decision-makers and stakeholders can use the results to derive strategies and measures to further promote a frictionless process. | [
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] | [
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10.1136/bmjqs-2013-001862 | [
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"Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.\nVITIS Healthcare Group, Cologne, Germany.",
"Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.\nVITIS Healthcare Group, Cologne, Germany.",
"Department of Hematology and Stem Cell Transplantation, Faculty of Medicine and University Hospital Essen, University of Duisburg-Essen, Essen, Germany.",
"Department of Hematology and Stem Cell Transplantation, Faculty of Medicine and University Hospital Essen, University of Duisburg-Essen, Essen, Germany.",
"Department of Hematology and Stem Cell Transplantation, West German Cancer Center and German Cancer Consortium (DKTK Partner Site Essen), University Hospital Essen, University of Duisburg-Essen, Essen, Germany.",
"Department of Hematology and Stem Cell Transplantation, Faculty of Medicine and University Hospital Essen, University of Duisburg-Essen, Essen, Germany.",
"Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.",
"Department of Hematology, Giessen and Marburg University Hospital (UKGM), Giessen, Germany.",
"Department of Hematology/Oncology and Stem-cell Transplantation, St Georg, Asklepios Hamburg, Hamburg, Germany.",
"Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.",
"Department of Hematology and Medical Oncology, Division for Stem Cell Transplantation and Cellular Therapy, University Hospital Göttingen, Göttingen, Germany.",
"Department of Internal Medicine III, Klinikum Chemnitz, Chemnitz, Germany.",
"Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.",
"VITIS Healthcare Group, Cologne, Germany.\nDepartment I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.\nFachhochschule für Oekonomie & Management (FOM) University of Applied Sciences, Essen, Germany."
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39376579 | 398 | Peptide-guided adaptor-CAR T-Cell therapy for the treatment of SSTR2-expressing neuroendocrine tumors. | Somatostatin receptor type 2 (SSTR2) is one of the five subtypes of somatostatin receptors and is overexpressed on the surface of most gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs), pituitary tumors, paraganglioma, and meningioma, as well as hepatocellular carcinoma and breast cancer. Chimeric antigen receptor (CAR) T-cells are genetically engineered to express an artificial, T-cell activating binder, leading upon ligation to biocidal activity against target-antigen expressing cells. Adaptor-CAR T-cells recognize, via the CAR, a tag on an antigen-binding molecule, building an activating bridge between the CAR and the target cell. We hypothesized that a novel fluorescent-peptide antagonist of SSTR2, called Octo-Fluo, in combination with anti-FITC adaptor CAR (AdFITC(E2)-CAR) T-cells, may function as an on-off tunable activating bridge between the CAR and SSTR2 expressing target cells. In vitro studies confirmed the binding of Octo-Fluo to Bon1-SSTR2 mCherry-Luc cells without evidence of internalization. AdFITC(E2)-CAR T-cells were activated and efficiently induced Bon1-SSTR2 cell death in vitro, in an Octo-Fluo concentration-dependent manner. Similarly, AdFITC(E2)-CAR T-cells in combination with Octo-Fluo efficiently infiltrated the tumor and eliminated Bon1-SSTR2 tumors in immunodeficient mice in therapeutic settings. Both, AdFITC(E2)-CAR T-cell tumor infiltration and biocidal activity were Octo-Fluo concentration-dependent, with high doses of Octo-Fluo, saturating both the CAR and the SSTR2 antigen independently, leading to the loss of tumor infiltration and biocidal activity due to the loss of bridge formation. Our findings demonstrate the potential of using AdFITC(E2)-CAR T-cells with Octo-Fluo as a versatile, on-off tunable bispecific adaptor for targeted CAR T-cell immunotherapy against SSTR2-positive NETs. | [
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"target cells",
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"breast cancer",
"high doses",
"an artificial, T-cell activating binder",
"combination",
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"the SSTR2 antigen"
] | [
"Adaptor-CAR T-cell",
"Octo-fluo bispecific adaptor",
"SSTR2",
"neuroendocrine tumors"
] | 0 | 10.1080/2162402X.2024.2412371
10.1001/jamaoncol.2017.0589
10.1507/endocrj.52.605
10.3390/molecules25235775
10.3389/fonc.2020.01633
10.18632/aging.202285
10.2967/jnumed.120.258897
10.1007/s00259-022-05771-3
10.1038/s41417-020-0196-5
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10.1210/clinem/dgad166 | [
"Pellegrino",
"Favalli",
"Volta",
"Benz",
"Puglioli",
"Bassi",
"Zitzmann",
"Auernhammer",
"Nölting",
"Magnani",
"Neri",
"Beuschlein",
"Manz"
] | [
"Department of Medical Oncology and Hematology, University Hospital Zürich (USZ) and University of Zürich (UZH), Comprehensive Cancer Center, Zürich, Switzerland.",
"Department of Chemistry, Philochem AG, Otelfingen, Switzerland.",
"Department of Medical Oncology and Hematology, University Hospital Zürich (USZ) and University of Zürich (UZH), Comprehensive Cancer Center, Zürich, Switzerland.",
"Department of Medical Oncology and Hematology, University Hospital Zürich (USZ) and University of Zürich (UZH), Comprehensive Cancer Center, Zürich, Switzerland.",
"Department of Chemistry, Philochem AG, Otelfingen, Switzerland.",
"Department of Chemistry, Philochem AG, Otelfingen, Switzerland.",
"Department of Medicine II, University-Hospital Munich-Grosshadern, University of Munich, Munich, Germany.",
"Department of Medicine II, University-Hospital Munich-Grosshadern, University of Munich, Munich, Germany.",
"Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zürich (USZ), University of Zürich (UZH), Zürich, Switzerland.",
"Department of Medical Oncology and Hematology, University Hospital Zürich (USZ) and University of Zürich (UZH), Comprehensive Cancer Center, Zürich, Switzerland.",
"Department of Chemistry, Philochem AG, Otelfingen, Switzerland.",
"Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zürich (USZ), University of Zürich (UZH), Zürich, Switzerland.\nDepartment of Internal Medicine IV and Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), Ludwig Maximilian University, LMU Klinikum, Munich, Germany.\nThe LOOP Zurich - Medical Research Center, Zürich, Switzerland.",
"Department of Medical Oncology and Hematology, University Hospital Zürich (USZ) and University of Zürich (UZH), Comprehensive Cancer Center, Zürich, Switzerland."
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39375047 | 399 | Therapeutic advantage of combinatorial CAR T cell and chemo-therapies. | Chimeric antigen receptor (CAR) T cell therapies have transformed outcomes for many patients with hematological malignancies. However, some patients do not respond to CAR T cell treatment, and adapting CAR T cells for solid and brain tumors has been met with many challenges including a hostile tumor microenvironment and poor CAR T cell persistence. Thus, it is unlikely that CAR T cell therapy alone will be sufficient for consistent, complete tumor clearance across cancer patients. Combinatorial therapies of CAR T cells and chemotherapeutics are a promising approach for overcoming this as chemotherapeutics could augment CAR T cells for improved anti-tumor activity or work in tandem with CAR T cells to clear tumors. Herein, we review efforts towards achieving successful CAR T cell and chemical drug combination therapies. We focus on combination therapies with approved chemotherapeutics as these will be more easily translated to the clinic, but also review non-approved chemotherapeutics and drug screens designed to reveal promising new CAR T cell and chemical drug combinations. Together, this review highlights the promise of CAR T cell and chemotherapy combinations with specific focus on how combinatorial therapy overcomes challenges faced by either monotherapy and supports the potential of this therapeutic strategy to improve outcomes for cancer patients. | [
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] | 2024-10-08 | 1 | 39375047 | [
"CAR T cell",
"CAR T cells",
"CAR T cell therapy",
"CAR T cell treatment",
"poor CAR T cell persistence",
"successful CAR T cell and chemical drug combination therapies",
"new CAR T cell and chemical drug combinations",
"combination therapies",
"approved chemotherapeutics",
"Combinatorial therapies",
"improved anti-tumor activity",
"many patients",
"many challenges",
"clear tumors",
"CAR",
"cancer patients",
"chemotherapy combinations",
"chemotherapeutics",
"non-approved chemotherapeutics and drug screens",
"how combinatorial therapy overcomes challenges",
"specific focus",
"outcomes",
"consistent, complete tumor clearance",
"a hostile tumor microenvironment",
"hematological malignancies",
"solid and brain tumors",
"tandem",
"efforts",
"this therapeutic strategy",
"some patients"
] | [
"chemotherapy",
"chimeric antigen receptors (CAR)",
"immunotherapy"
] | 0 | 10.1124/pharmrev.124.001070 | [
"Ward",
"Jones",
"Krenciute"
] | [
"St. Jude Children's Research Hospital, United States.",
"St. Jude Children's Research Hospital, United States.",
"St Jude Children's Research Hospital, United States [email protected]."
] | [
"39375047"
] | [] | 9.926025 | 4.643299 |
Subsets and Splits