Improving immunotherapy in bladder cancer by targeting immune dysfunction

描述（由申请人提供）：候选人的长期职业目标是成为一名独立资助的医生-科学家，积极参与将基础研究成果转化为临床治疗。拟议的职业发展计划将教学课程与癌症免疫学研究的设计和进行中的指导研究经验相结合，为候选人提供在以患者为导向的研究中成功职业生涯的必要组成部分。候选人的教育目标是：1）培养先进研究方法的技能，并形成合作，使深入和高影响力的转化研究成为可能; 2）了解BCG抗肿瘤活性的潜在免疫机制; 3）将研究结果转化为临床实践，为膀胱癌患者提供膀胱切除的替代方案。此外，在泰勒Curiel和伊恩·汤普森博士的指导下，候选人将培养专业能力，包括赠款写作，有效的实验室管理，以及对研究伦理的更好理解。这项研究的目的是研究BCG免疫疗法的潜在T细胞机制，以帮助确定治疗膀胱癌的新方法。中心假设是抗原特异性免疫有助于BCG在膀胱癌中的临床活性。提出了一种新的策略，使用mTOR抑制剂雷帕霉素，以提高抗原特异性免疫和提高BCG的抗肿瘤作用。计划中的工作为后续研究奠定了基础，以测试雷帕霉素/BCG策略的潜在机制，并使用该奖项期间开发的方法和经验进行I/II期疗效试验。将检验三个假设：1）肿瘤特异性免疫有助于BCG功效; 2）BCG特异性免疫有助于BCG功效; 3）雷帕霉素改善BCG功效并增强抗原特异性免疫。该方法具有重要意义，因为它提出了膀胱癌细胞可以表达BCG抗原的新概念，使BCG特异性免疫能够杀死这些膀胱癌细胞。该方法是创新的，因为该提案是对癌症中mTOR抑制的当前范式的转变，其中重点是直接抗肿瘤作用。

DESCRIPTION (provided by applicant): 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.