Engineered Chimeric Antigen Receptors for Photo-Tunable Remote Control of CAR T-Cells

Chimeric antigen receptor (CAR) T-cell immunotherapy has demonstrated high potential for elimination of tumors, particularly in patients with CD19-positive lymphoma and leukemia. CARs are synthetic receptors engineered onto the surface of T cells, where they can engage specific tumor antigens in a major histocompatibility complex (MHC)-independent manner. The recognition of antigen allows T cells to be activated and subsequently perform their killing/effector activities toward tumor cells. Despite the tremendous success of CAR T-cell therapy in cancer treatment, this type of immunotherapy imposes significant safety challenges, as most notably exemplified by the cytokine release syndrome (CRS) and the on-target, off-tumor cytotoxicity due to the lack of precise control over the location and duration of anti-tumor immune response. Herein we present the design of light-switchable CAR T-cell (designated LiCAR) that enables photo-tunable activation of therapeutic T cells to induce tumor cell killing both in vitroand in vivo. When coupled with imaging guided surgically removable upconversion nanoplates that have enhanced near infrared (NIR)-to-blue upconversion luminescence as miniatured deep tissue transducers, LiCAR enables precise spatiotemporal control over CAR T cell-mediated anti-tumor therapeutic activity. This remotely controllable nano-optogenetic device sets the stage for the exploration of optogenetic immunotherapy to deliver personalized anti-cancer therapy.