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Depletion of Tregs from CD4 CAR-T cells enhances the tumoricidal effect of CD8 CAR-T cells in anti-CD19 CAR-T therapy.
FEBS J
December 2024
Department of Hematology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital Yunnan, Kunming, China.
Chimeric antigen receptor T (CAR-T) cell therapy, which targets CD19 for hematological malignancies, represents a breakthrough in cancer immunotherapy. However, some patients may develop resistance to CAR-T treatment, underscoring the importance of optimizing CAR-T design to enhance responsiveness. Here, we investigated the impact of different subpopulations in anti-CD19 CAR-T cells on the tumoricidal effect.
View Article and Find Full Text PDFAntibiotic-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).
View Article and Find Full Text PDFOptimizing Transfection Efficiency in CAR-T Cell Manufacturing through Multiple Administrations of Lipid-Based Nanoparticles.
ACS Appl Bio Mater
June 2024
Department of Molecular Medicine, Sapienza University of Rome, V.le Regina Elena 291, Rome 00161, Italy.
The existing manufacturing protocols for CAR-T cell therapies pose notable challenges, particularly in attaining a transient transfection that endures for a significant duration. To address this gap, this study aims to formulate a transfection protocol utilizing multiple lipid-based nanoparticles (LNPs) administrations to enhance transfection efficiency (TE) to clinically relevant levels. By systematically fine-tuning and optimizing our transfection protocol through a series of iterative refinements, we have accomplished a remarkable one-order-of-magnitude augmentation in TE within the immortalized T-lymphocyte Jurkat cell line.
View Article and Find Full Text PDFIncorporating radiation with anti-CD19 chimeric antigen receptor T-cell therapy for relapsed/refractory non-Hodgkin lymphoma: A multicenter consensus approach.
Am J Hematol
January 2024
Department of Radiation Oncology, Mayo Clinic, Jacksonville, Florida, USA.
Anti-CD19 chimeric antigen receptor T-cell therapy (CART) has revolutionized the outcomes of relapsed and/or refractory B-cell non-Hodgkin lymphoma. However, CART is still limited by its availability, toxicity, and response durability. Not all patients make it to the CART infusion phase due to disease progression.
View Article and Find Full Text PDFDevelopment of a multiscale mechanistic modeling framework integrating differential cellular kinetics of CAR T-cell subsets and immunophenotypes in cancer patients.
CPT Pharmacometrics Syst Pharmacol
September 2023
Clinical Pharmacology and Modeling, Precision and Translational Medicine, Oncology Cell Therapy and Therapeutic Area Unit, Takeda Pharmaceuticals, Cambridge, Massachusetts, USA.
Chimeric antigen receptor (CAR) T-cell subsets and immunophenotypic composition of the pre-infusion product, as well as their longitudinal changes following infusion, are expected to affect CAR T-cell expansion, persistence, and clinical outcomes. Herein, we sequentially evolved our previously described cellular kinetic-pharmacodynamic (CK-PD) model to incorporate CAR T-cell product-associated attributes by utilizing published preclinical and clinical datasets from two affinity variants (FMC63 and CAT19 scFv) anti-CD19 CAR T-cells. In step 1, a unified cell-level PD model was used to simultaneously characterize the in vitro killing datasets of two CAR T-cells against CD19+ cell lines at varying effector:target ratios.
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