T cell therapies are still hindered by poor T cell persistence and function, making them largely ineffective against solid tumors. Human cancerous T cells acquire mutations that increase their fitness and evade immune challenges in similar situations to those faced by therapeutic T cells. Writing in Nature, Garcia and colleagues exploit the fitness-enhancing abilities of these cancer mutations by incorporating them into engineered therapeutic T cells for improved performance.

The authors screened 71 cancerous T cells mutations for their potential effect on therapeutic T cell function. Among these candidates, they identified a gene fusion, CARD11–PIK3R3, that significantly improved anti-tumor activity of T cell therapies in mouse models bearing various cancers, including melanoma. CARD11–PIK3R3 improved the efficacy of both T cell receptor (TCR) and chimeric antigen receptor (CAR)-T cell therapy by amplifying signaling through CBM, a complex that is essential for T cell activation and function in response to antigens. The mutated T cells also improved general treatment conditions, requiring lower dosing and eliminating the need for lymphodepletion chemotherapy — a procedure that is often used to improve T cell therapy effectiveness but is associated with substantial toxicities.