Improving Immunotherapy in Bladder Cancer by Targeting Immune Dysfunction

The candidate's long-term career goal is to become an independently funded physician- scientist who is actively engaged in translating basic research findings into clinical therapeutics. The proposed career development plan integrates didactic coursework with mentored research experience in the design and conduct of cancer immunology research to provide the candidate with the necessary components for a successful career in patient-oriented research. The candidate's educational aims are to 1) To develop skills in advanced research methodologies and form collaborations that will enable in-depth and high-impact translational studies; 2) understand potential immune mechanisms underlying BCG's antitumor activity; 3) translate research findings into clinical practice with the goal of providin an alternative to bladder removal for patients with bladder cancer. In addition, under the mentorship of Drs. Tyler Curiel and Ian Thompson, the candidate will cultivate professional aptitudes including grant writing, efficient laboratory management, and an improved understanding of ethics in research. The objective of the proposed research is to examine potential T cell mechanisms underlying BCG immunotherapy in order to aid in identifying novel approaches for treating bladder cancer. The central hypothesis is that antigen-specific immunity contributes to the clinical activity of BCG in bladder cancer. A novel strategy is proposed using the mTOR inhibitor, rapamycin, to boost antigen-specific immunity and improve BCG's antitumor effects. The work as planned sets the stage for follow up studies to test mechanisms underlying the rapamycin/BCG strategy and to conduct a phase I/II efficacy trial using methods and experience developed during this award. Three hypotheses will be tested: 1) tumor-specific immunity contributes to BCG efficacy; 2) BCG-specific immunity contributes to BCG efficacy; 3) rapamycin improves BCG efficacy and boosts antigen-specific immunity. The approach is significant because it advances the novel concept that bladder cancer cells can express BCG antigens enabling BCG-specific immunity to kill these bladder cancer cells. The approach is innovative because the proposal is a shift from the current paradigms on mTOR inhibition in cancer, where the focus has been on direct anti-tumor effects. PUBLIC HEALTH RELEVANCE: Bladder cancer has been termed the most expensive cancer to manage because of the high relapse rates and need for repeated monitoring. Novel strategies to improve treatments for bladder cancer therefore have important implications for the public health in general.