BCCMA: Translational research to improve the care of advanced bladder cancer

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Sub-Title of This Project Development of an oral cancer-specific quadra-functional theranostic platform for advanced bladder cancer SUMMARY Bladder cancer is the fourth most common cancer and seventh most common cause of cancer death in men. Almost all bladder cancer deaths are caused by advanced bladder cancer (aBC) which is the focus of this project. Immunotherapy with immune checkpoint inhibitors (ICIs) is only moderately effective, costly, inconveniently administrated through intravenous infusion and associated with significant immune-mediated toxicity secondary to delivery of ICIs to and activation of immune response against non-cancerous tissues. The goal of this project is to develop oral cancer-specific theranostic platform that can not only deliver an ICI to cancer sites with enhanced efficacy, decreased toxicity, low cost and convenient oral administration, but can also be used for photodynamic diagnosis and therapy. In this project, cancer-specific attenuated Salmonella will specifically deliver a protein photosensitizer to cancer sites which is then activated by light to emit red fluorescence for photodynamic diagnosis, and to produce reactive oxygen species (ROS) for photodynamic therapy. Salmonella itself can also modify and create pro-immune tumor microenvironment (microbiotherapy). Furthermore, the cancer-specific Salmonella can express an ICI locally at the cancer sites to activate anti- cancer immunity while eliminating immune-mediated toxicity associated with intravenous immunotherapy. More importantly, photodynamic therapy, microbiotherapy and immunotherapy can achieve synergistic anti-cancer effects and enhance the efficacy. Four specific aims are proposed in this project. Aim I is to determine the most effective cancer-specific Salmonella regimen for bladder cancer immunotherapy; Aim II is to determine whether the cancer-specific Salmonella can eradicate locally advanced bladder cancer, induce abscopal effect, and prevent cancer metastasis; Aim III is to determine the underlying mechanisms of action and resistance; and Aim IV is to determine the potential of the cancer-specific Salmonella for photodynamic diagnosis. Accomplishment of the proposed work will lead to the consultation with the US Food and Drug Administration for clinical trials in human patients.