An NK-like CAR T cell transition in CAR T cell dysfunction.

This study highlights the transition of CAR T cells to an NK-like state in pancreatic cancer, suggesting that targeting specific transcription factors may improve CAR T cell function, though specific outcomes are not detailed.

Summary and findings

This study investigates the dysfunction of mesothelin-redirected CAR T cells in pancreatic cancer, focusing on the transition of CD8+ T cells to NK-like T cells. The research identifies key transcription factors associated with CAR T cell exhaustion and suggests genetic modulation as a potential strategy to enhance CAR T cell efficacy. No specific numeric outcomes or treatment claims are provided.

Abstract

Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable success in hematological malignancies but remains ineffective in solid tumors, due in part to CAR T cell exhaustion in the solid tumor microenvironment. To study dysfunction of mesothelin-redirected CAR T cells in pancreatic cancer, we establish a robust model of continuous antigen exposure that recapitulates hallmark features of T cell exhaustion and discover, both in vitro and in CAR T cell patients, that CAR dysregulation is associated with a CD8+ T-to-NK-like T cell transition. Furthermore, we identify a gene signature defining CAR and TCR dysregulation and transcription factors, including SOX4 and ID3 as key regulators of CAR T cell exhaustion. Our findings shed light on the plasticity of human CAR T cells and demonstrate that genetic downmodulation of ID3 and SOX4 expression can improve the efficacy of CAR T cell therapy in solid tumors by preventing or delaying CAR T cell dysfunction.

Elsewhere in the Tesa IPA Protocol (Tesa-IPA) corpus