Search

Poor CAR T persistence limits CAR T cell therapies for B cell malignancies and solid tumors 1,2 . The expression of memory-associated genes such as TCF7 (protein name TCF1) is linked to response and long-term persistence in patients 3-7 , thereby implicating memory programs in therapeutic efficacy. Here, we demonstrate that the pioneer transcription factor, FOXO1, is responsible for promoting memory programs and restraining exhaustion in human CAR T cells. Pharmacologic inhibition or gene editing of endogenous FOXO1 in human CAR T cells diminished the expression of memory-associated genes, promoted an exhaustion-like phenotype, and impaired antitumor activity in vitro and in vivo . FOXO1 overexpression induced a gene expression program consistent with T cell memory and increased chromatin accessibility at FOXO1 binding motifs. FOXO1-overexpressing cells retained function, memory potential, and metabolic fitness during settings of chronic stimulation and exhibited enhanced persistence and antitumor activity in vivo . In contrast, TCF1 overexpression failed to enforce canonical memory programs or enhance CAR T cell potency. Importantly, endogenous FOXO1 activity correlated with CAR T and TIL responses in patients, underscoring its clinical relevance in cancer immunotherapy. Our results demonstrate that memory reprogramming through FOXO1 can enhance the persistence and potency of human CAR T cells and highlights the utility of pioneer factors, which bind condensed chromatin and induce local epigenetic remodeling, for optimizing therapeutic T cell states., Competing Interests: Competing interests: C.A.L. is a consultant to Cartography Biosciences. S.A.G. receives research funding from Novartis, Kite, Vertex, and Servier and consults for Novartis, Roche, GSK, Humanigen, CBMG, Eureka, Janssen/JNJ, and Jazz Pharmaceuticals and has advised for Novartis, Adaptimmune, TCR2, Cellctis, Juno, Vertex, Allogene, Jazz Pharmaceuticals, and Cabaletta. J.A.F. receives research funding from Tceleron (formerly Tmunity Therapeutics) and Danaher Corporation and consults for Retro Biosciences, and is a member of the Scientific Advisory Boards of Cartography Bio and Shennon Biotechnologies Inc. A.T.S. is a founder of Immunai and Cartography Biosciences and receives research funding from Allogene Therapeutics and Merck Research Laboratories. C.L.M. is a co-founder of and holds equity in Link Cell Therapies, is a co-founder of and holds equity in Cargo Therapeutics (formerly Syncopation Life Sciences), is a co-founder of and holds equity in Lyell Immunopharma, holds equity and consults for Mammoth and Ensoma, consults for Immatics, Nektar, and receives research funding from Tune Therapeutics. E.W.W. is a consultant for and holds equity in Lyell Immunopharma and consults for Umoja Immunopharma.