Rejuvenating Effector/Exhausted CAR T Cells to Stem Cell Memory–Like CAR T Cells By Resting Them in the Presence of CXCL12 and the NOTCH Ligand

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Abstract

T cells with a stem cell memory (TSCM) phenotype provide long-term and potent antitumor effects for T-cell transfer therapies. Although various methods for the induction of TSCM-like cells in vitro have been reported, few methods generate TSCM-like cells from effector/exhausted T cells. We have reported that coculture with the Notch ligand–expressing OP9 stromal cells induces TSCM-like (iTSCM) cells. Here, we established a feeder-free culture system to improve iTSCM cell generation from expanded chimeric antigen receptor (CAR)-expressing T cells; culturing CAR T cells in the presence of IL7, CXCL12, IGF-I, and the Notch ligand, hDLL1. Feeder-free CAR-iTSCM cells showed the expression of cell surface markers and genes similar to that of OP9-hDLL1 feeder cell–induced CAR-iTSCM cells, including the elevated expression of SCM-associated genes, TCF7, LEF1, and BCL6, and reduced expression of exhaustion-associated genes like LAG3, TOX, and NR4A1. Feeder-free CAR-iTSCM cells showed higher proliferative capacity depending on oxidative phosphorylation and exhibited higher IL2 production and stronger antitumor activity in vivo than feeder cell–induced CAR-iTSCM cells. Our feeder-free culture system represents a way to rejuvenate effector/exhausted CAR T cells to SCM-like CAR T cells. Significance: Resting CAR T cells with our defined factors reprograms exhausted state to SCM-like state and enables development of improved CAR T-cell therapy.

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APA

Ando, M., Kondo, T., Tomisato, W., Ito, M., Shichino, S., Srirat, T., … Yoshimura, A. (2021). Rejuvenating Effector/Exhausted CAR T Cells to Stem Cell Memory–Like CAR T Cells By Resting Them in the Presence of CXCL12 and the NOTCH Ligand. Cancer Research Communications, 1(1), 41–55. https://doi.org/10.1158/2767-9764.CRC-21-0034

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