To improve CAR T cell products currently used in phase I clinical trials for the treatment of solid tumors, Meyran and Zhu et al. developed a protocol to generate TSTEM-like CAR T cells with a distinct memory T cell progenitor gene expression profile. TSTEM-like CAR T cells demonstrated improved proliferative capacity and cytokine section, even after chronic antigen stimulation in vitro, and increased persistence and tumor control in subcutaneous and orthotopic NSG models, which was enhanced in combination with anti-PD-1. The presence of CD4+ T cells during the CAR T cell production phase was crucial for the generation of fully functional CD8+ TSTEM-like CAR T cells.
Contributed by Ute Burkhardt
ABSTRACT: Patients who receive chimeric antigen receptor (CAR)-T cells that are enriched in memory T cells exhibit better disease control as a result of increased expansion and persistence of the CAR-T cells. Human memory T cells include stem-like CD8+ memory T cell progenitors that can become either functional stem-like T (TSTEM) cells or dysfunctional T progenitor exhausted (TPEX) cells. To that end, we demonstrated that TSTEM cells were less abundant in infused CAR-T cell products in a phase 1 clinical trial testing Lewis Y-CAR-T cells (NCT03851146), and the infused CAR-T cells displayed poor persistence in patients. To address this issue, we developed a production protocol to generate TSTEM-like CAR-T cells enriched for expression of genes in cell replication pathways. Compared with conventional CAR-T cells, TSTEM-like CAR-T cells had enhanced proliferative capacity and increased cytokine secretion after CAR stimulation, including after chronic CAR stimulation in vitro. These responses were dependent on the presence of CD4+ T cells during TSTEM-like CAR-T cell production. Adoptive transfer of TSTEM-like CAR-T cells induced better control of established tumors and resistance to tumor rechallenge in preclinical models. These more favorable outcomes were associated with increased persistence of TSTEM-like CAR-T cells and an increased memory T cell pool. Last, TSTEM-like CAR-T cells and anti-programmed cell death protein 1 (PD-1) treatment eradicated established tumors, and this was associated with increased tumor-infiltrating CD8+CAR+ T cells producing interferon-γ. In conclusion, our CAR-T cell protocol generated TSTEM-like CAR-T cells with enhanced therapeutic efficacy, resulting in increased proliferative capacity and persistence in vivo.
Author Info: (1) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia. Universit de Paris, Inserm, U976 HIPI Unit, Institut de Recherche Saint-Louis, Paris F-750
Author Info: (1) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia. Universit de Paris, Inserm, U976 HIPI Unit, Institut de Recherche Saint-Louis, Paris F-75010, France. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia. (2) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia. (3) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia. (4) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia. (5) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia. (6) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia. (7) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia. (8) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia. (9) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia. (10) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia. (11) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia. (12) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia. (13) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia. (14) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia. (15) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia. (16) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia. (17) Tumor Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Austin Health, Heidelberg, VIC 3084, Australia. School of Cancer Medicine, La Trobe University, Melbourne, VIC 3086, Australia. (18) Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW 1466, Australia. (19) Division of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (20) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia. Division of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (21) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia. Division of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (22) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia. Division of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (23) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia. (24) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia. (25) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia. Division of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (26) Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia. Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW 1466, Australia. School of Women's and Children's Health, UNSW Sydney, Sydney, NSW 1466, Australia. Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW 2031, Australia. Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia. (27) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia. (28) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia. (29) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia.
