UCSF

Adoptive T cell therapies have produced exceptional responses in a subset of cancer patients. However, therapeutic efficacy can be hindered by poor T cell persistence and function. In human T cell cancers, evolution of the disease positively selects for mutations that improve fitness of T cells in challenging situations analogous to those faced by therapeutic T cells. Therefore, we hypothesized that many of these mutations could be co-opted to improve T cell therapies. Through systematic screening we identify a gene fusion, CARD11-PIK3R3, found in a CD4+ cutaneous T cell lymphoma that augments CARD11-BCL10-MALT1 complex signaling to increase anti-tumor efficacy of therapeutic T cells in multiple xenograft models. Inclusion of CARD11-PIK3R3 also dramatically improves CAR therapy in immunologically cold syngeneic models, without the requirement for pre-conditioning. Furthermore, CAR + CARD11-PIK3R3 therapy induces significant changes within the periphery and tumor microenvironment (TME), shifting cold tumors towards a state of greater inflammation and recruiting infiltration of the endogenous immune system.In parallel to the discovery of CARD11-PIK3R3, we developed a new class of synthetic receptors called SNIPR CARs. These receptors induce short timescale signaling and long term custom transcriptional responses in a single receptor architecture, providing researchers with the ability to redirect patient T cells against cancerous cells while simultaneously delivering payloads to counteract challenges encountered in cancers. We have paired these receptors with payloads such as CARD11-PIK3R3, and found they induce sufficient CAR activity and antigen restricted payload expression, resulting in improved anti-tumor efficacy with a hypothesized more favorable safety profile. Altogether, these results indicate that exploiting naturally occurring mutations represents a promising approach for improving T cell therapies, particularly in cold solid tumor microenvironments where few therapies have made impact. Additionally, we suggest that engineering solutions, such as SNIPR CARs, can allow us to tune or control potent but oncogenic sourced or systemically toxic modifiers, to create highly safe and efficacious cell therapies.