Exploiting T cell lymphoma mutations enhances engineered T cell therapies

We systematically screened the effects of 71 mutations from T cell lymphomas on T cell signaling, cytokine production, and in vivo persistence in tumors. We identify a gene fusion, CARD11-PIK3R3, found in a CD4+ cutaneous T cell lymphoma2 that augments CARD11-BCL10-MALT1 complex signaling to increase anti-tumor efficacy of therapeutic T cells in multiple immunotherapy refractory models. Our results indicate that exploiting naturally occurring mutations represents a promising approach to explore the extremes of T cell biology and discover how solutions derived from evolution of malignant T cells can improve a broad range of T cell therapies.