Ming-Ru Wu, MD, PhD

Dana-Farber Cancer Institute

Academic Titles

Assistant Professor, Immunology, Harvard Medical School

Research Program Affiliation

Member, Developmental Therapeutics

Member, Cancer Immunology

Research Abstract

Direction 1: Develop a cancer-targeting gene circuit platform for triggering tumor-localized immunotherapy. Cancer immunotherapies have demonstrated great potential but still face significant challenges when treating solid tumors. One major hurdle is that solid tumors create hard to penetrate tumor masses and an immunosuppressive tumor microenvironment (TME) that limits immune cell recruitment, infiltration, and activation. To overcome these challenges, we have developed a programmable synthetic gene circuit platform that enables tumor-localized therapeutic payload production, for recruitment and activation of immune cells: Tumor Immunotherapy by Gene-circuit Engineered Response (TIGER). Briefly, these gene circuits can be encoded in viruses or plasmids and be delivered into the body. Once the circuits enter cells, they will sense several pre-defined intracellular tumor signatures and determine whether the cell is cancerous and trigger an effective tumor-localized combinatorial immunotherapy, and prevent damage to healthy cells. Importantly, we have demonstrated that TIGER mediates robust therapeutic efficacy in vivo in solid tumor mouse models, even when only a small fraction of tumor cells were delivered with the circuits. To further accomplish clinical translation of this platform, We are currently focusing on: 1) identifying tumor sensors that detect heterogeneous primary patient tumors, to optimize tumor-targeting specificity; 2) optimizing therapeutic output combinations for achieving maximal efficacy; 3) encoding circuits into FDA-approved viral vehicles to enhance delivery efficiency. These efforts will facilitate the clinical translation of TIGER to treat solid tumors and overcome existing barriers to effective immunotherapy. Direction 2: Develop a chimeric antigen receptor (CAR)-T cell platform with enhanced therapeutic efficacy and safety. Current FDA approved CAR-T cell therapies exhibit tremendous potential in treating blood cancers. However, challenges such as 1) the lack of ideal targetable tumor antigens; 2) severe toxicity due to off-target effects; and 3) tumor-mediated immunosuppression limit the application of CAR-T cells to treat solid tumors. Approaches to address each challenge, such as logic-gated tumor antigen recognition, safety switch, or immunostimulatory payload secreting CAR-T cells, have been developed independently. However, integrating these systems into a single system is challenging. We aim to develop an integrated and innovative CAR-T platform. We are currently focusing on: 1) developing sense and respond gene circuits for CAR-T cell to enhance targeting specificity and therapeutic efficacy; and 2) creating switches to enhance the safety profile of CAR-T cell. These efforts will empower CAR-T cell to effectively treat solid tumors.