T STEM -like CAR-T cells exhibit improved persistence and tumor control compared with conventional CAR-T cells in preclinical models.

Autor: Meyran D; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia.; Université 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., Zhu JJ; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia., Butler J; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia., Tantalo D; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia., MacDonald S; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia., Nguyen TN; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia., Wang M; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia., Thio N; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia., D'Souza C; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia., Qin VM; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia., Slaney C; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia., Harrison A; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia., Sek K; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia., Petrone P; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia., Thia K; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia., Giuffrida L; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia., Scott AM; 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., Terry RL; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW 1466, Australia., Tran B; Division of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia., Desai J; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia.; Division of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia., Prince HM; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia.; Division of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia., Harrison SJ; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia.; Division of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia., Beavis PA; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia., Kershaw MH; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia., Solomon B; 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., Ekert PG; 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., Trapani JA; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia., Darcy PK; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia., Neeson PJ; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia.
Jazyk: angličtina
Zdroj: Science translational medicine [Sci Transl Med] 2023 Apr 05; Vol. 15 (690), pp. eabk1900. Date of Electronic Publication: 2023 Apr 05.
DOI: 10.1126/scitranslmed.abk1900
Abstrakt: 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 (T STEM ) cells or dysfunctional T progenitor exhausted (T PEX ) cells. To that end, we demonstrated that T STEM 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 T STEM -like CAR-T cells enriched for expression of genes in cell replication pathways. Compared with conventional CAR-T cells, T STEM -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 T STEM -like CAR-T cell production. Adoptive transfer of T STEM -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 T STEM -like CAR-T cells and an increased memory T cell pool. Last, T STEM -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 T STEM -like CAR-T cells with enhanced therapeutic efficacy, resulting in increased proliferative capacity and persistence in vivo.
Databáze: MEDLINE
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