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

2023; American Association for the Advancement of Science; Volume: 15; Issue: 690 Linguagem: Inglês

10.1126/scitranslmed.abk1900

1946-6242

Déborah Meyran, Joe Jiang Zhu, Jeanne Butler, Daniela Tantalo, Sean Macdonald, Thu Ngoc Nguyen, Minyu Wang, Niko Thio, Criselle D’Souza, Vicky Mengfei Qin, Clare Y. Slaney, Aaron J Harrison, Kevin Sek, Pasquale Petrone, Kevin Thia, Lauren Giuffrida, Andrew M. Scott, Rachael Terry, Ben Tran, Jayesh Desai, H. Miles Prince, Simon J. Harrison, Paul A. Beavis, Michael H. Kershaw, Benjamin Solomon, Paul G. Ekert, Joseph A. Trapani, Phillip K. Darcy, Paul J. Neeson,

Viral Infectious Diseases and Gene Expression in Insects

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.