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Title: TSTEM-like CAR-T cells exhibit improved persistence and tumor control compared with conventional CAR-T cells in preclinical models.
Austin Authors: Meyran, Deborah;Zhu, Joe Jiang;Butler, Jeanne;Tantalo, Daniela;MacDonald, Sean;Nguyen, Thu Ngoc;Wang, Minyu;Thio, Niko;D'Souza, Criselle;Qin, Vicky Mengfei;Slaney, Clare;Harrison, Aaron;Sek, Kevin;Petrone, Pasquale;Thia, Kevin;Giuffrida, Lauren;Scott, Andrew M ;Terry, Rachael L;Tran, Ben;Desai, Jayesh;Prince, H Miles;Harrison, Simon J;Beavis, Paul A;Kershaw, Michael H;Solomon, Ben;Ekert, Paul G;Trapani, Joseph A;Darcy, Phillip K;Neeson, Paul J
Affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia.;
Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia.
Université de Paris, Inserm, U976 HIPI Unit, Institut de Recherche Saint-Louis, Paris F-75010, France
Intensive Care
School of Cancer Medicine, La Trobe University, Melbourne, VIC 3086, Australia.
Olivia Newton-John Cancer Research Institute
Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW 1466, Australia.
Division of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3000, Australia.;Division of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, 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.
School of Women's and Children's Health, UNSW Sydney, Sydney, NSW 1466, Australia.
Issue Date: 5-Apr-2023
Date: 2023
Publication information: Science Translational Medicine 2023-04-05; 15(690)
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.
DOI: 10.1126/scitranslmed.abk1900
ORCID: 0000-0003-2723-8185
Journal: Science Translational Medicine
Start page: eabk1900
PubMed URL: 37018415
ISSN: 1946-6242
Type: Journal Article
Subjects: Immunotherapy, Adoptive/methods
Stem Cells/metabolism
Receptors, Antigen, T-Cell/metabolism
Appears in Collections:Journal articles

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