Enhancing mitochondrial metabolism to improve anti-tumor CD8 immune response

SUMMARY CAR-T immunotherapy has great promise as a salvage regimen for patients who will no longer respond to conventional therapies. Five CAR-T cell therapies (four targeting CD19 on cancer cells) have been approved by FDA for treatment of relapsed and/or refractory (r/r) B-lineage malignancies, including ALL, Non-Hodgkin Lymphoma, CLL and multiple myeloma. However, about 50% of B cell leukemia and lymphoma patients treated with CD19 CAR-T therapy relapse within a year after CAR-T therapy. The success of CAR-T therapy has been associated with several factors, including: 1) the initial expansion of CAR-T cells after transfer into the patients in an IL-2-deprived environment, 2) maintenance of the CAR-T cell effector function 3) long-term survival of CAR-T cells. These T cell biology aspects are highly influence by their metabolic stage, and CAR-T cell outcome is known to be influenced by their metabolism. Metabolism is now considered as a major regulatory factor of the function of immune cells and influences the course of an immune response. We have identified MCJ (Methylation-Controlled J protein) as a protein localized in the inner membrane of mitochondria that acts as an endogenous negative regulator of Complex I and mitochondrial respiration (mitochondrial ATP production). We have shown that loss of MCJ in CD8 cells enhances cytokine secretion as well as cytotoxic activity. Memory MCJ KO CD8 cells have superior protective activity against influenza virus. MCJ deficient CD8 cells are also more efficient in killing tumor cells. Thus, we hypothesize that eliminating MCJ as a metabolic brake in CD8 cells will result in enhanced cytokine production, tumor killing activity and survival of CAR-T cells and that MCJ could be an attractive target to improve the success of CAR-T immunotherapy. To test this hypothesis and show its clinical relevance, we propose: 1) to evaluate the role of MCJ as a regulator of mitochondrial metabolism and effector function in human CD8 cells; 2) to evaluate the in vitro and vivo potency and efficacy of mouse MCJ-deficient CAR T cells, 3) to develop an MCJ-deficient human CD8 CAR-T with improved survival, expansion and cytotoxic activity.