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

Meyran, D; Zhu, JJ; Butler, J; Tantalo, D; Macdonald, S; Nguyen, TN; Wang, M; Thio, N; D&#39;Souza, C; Qin, VM; Slaney, C; Harrison, A; Sek, K; Petrone, P; Thia, K; Giuffrida, L; Scott, AM; Terry, RL; Tran, B; Desai, J; Prince, HM; Harrison, SJ; Beavis, PA; Kershaw, MH; Solomon, B; Ekert, PG; Trapani, JA; Darcy, PK; Neeson, PJ

Author(s): Meyran, D; Zhu, JJ; Butler, J; Tantalo, D; Macdonald, S; Nguyen, TN; Wang, M; Thio, N; D'Souza, C; Qin, VM; Slaney, C; Harrison, A; Sek, K; Petrone, P; Thia, K; Giuffrida, L; Scott, AM; Terry, RL; Tran, B; Desai, J; Prince, HM; Harrison, SJ; Beavis, PA; Kershaw, MH; Solomon, B; Ekert, PG; Trapani, JA; Darcy, PK; Neeson, PJ;
Details: Publication Year 2023-04-05,Volume 15,Issue #690,Page eabk1900
Journal Title: Science Translational Medicine
Publication Type: Research article
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 (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-gamma. 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.
Publisher: American Association for the Advancement of Science
Keywords: Humans; *Immunotherapy, Adoptive/methods; *Neoplasms; T-Lymphocytes; Cytokines/metabolism; Stem Cells/metabolism; Receptors, Antigen, T-Cell/metabolism
Department(s): Laboratory Research; Medical Oncology
PubMed ID: 37018415
Publisher's Version: https://doi.org/10.1126/scitranslmed.abk1900
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-08-03 07:58:24

Last Modified: 2023-08-03 08:01:33