Modulating T Cell Metabolism to Improve CAR-T Cell Therapy success

Abstract

Abstract Chimeric antigen receptor (CAR)-T cell therapy is a promising treatment for lymphoblastic leukemia and lymphoma. Despite initial response to CAR-T cell therapy, about 40% of patients relapse. Modulating CAR-T cell metabolism (immunometabolism) is being considering as a novel approach to improve CAR-T cell therapy efficacy. We have identified MCJ (DnaJC15) as a novel target to enhance CAR-T cell mitochondrial metabolism. MCJ is an endogenous negative regulator of Complex I of electron transport chain. The absence of MCJ in MCJ KO CD8 cells increases Complex I activity, mitochondrial membrane potential, and mitochondrial respiration without affecting glycolysis or ROS production. Lack of MCJ also enhances ATP-dependent effector functions of CD8 cells, including cytokine secretion and cytotoxicity. Using the B16 melanoma cell model, we have shown that antigen-specific MCJ KO CD8 cells are superior in eliminating melanoma cells through enhanced effector function in vitro and in vivo. Importantly, we have generated MCJ-deficient CD8 CAR-T cells against CD19+ B cell leukemia and shown that they exhibit superior killing capacity through their increase cytotoxicity activity in vitro. MCJ KO CAR-T cells have higher mitochondrial maximal respiration and spare respiratory capacity. Furthermore, in vivo MCJ KO CAR-T cells have superior efficacy than WT CAR-T cells, and increase overall survival of the leukemia-bearing mice. Together, these data demonstrate MCJ as a novel target to enhance CAR-T cell therapy efficacy. To show the translational relevance of our studies and moving forward to the clinic, we are currently investigating whether silencing MCJ in human CD8 CAR-T cells also improve their efficacy. R21 AI110016 R21 AI149187 R56 AI148434 R01 CA260909 R21 CA223389