Transcription Factors Driving CAR T Cell Dysfunction

Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable success in hematological malignancies. Yet, it remains ineffective in solid tumors due in part to CAR T cell exhaustion in the solid tumor microenvironment. In this GEN webinar, we will learn how our guest presenter, Dr. Charly Ryan Good, studies the dysfunction of mesothelin-redirected CAR T cells in pancreatic cancer. Dr. Good will tell us how she and her colleagues established 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. Additionally, she will describe how they identified a gene signature defining CAR and TCR dysregulation and transcription factors, including SOX4 and ID3, as key regulators of CAR T cell exhaustion. Their 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.

A live Q&A session followed the presentation, offering a chance to pose questions to our expert panelist.