Improving immunotherapy in bladder cancer by targeting immune dysfunction

描述(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内科科学家，积极致力于将基础研究成果转化为临床疗法。拟议的职业发展计划将教学课程与癌症免疫学研究设计和实施方面的指导研究经验相结合，为应聘者提供在以患者为导向的研究中成功职业生涯所必需的组成部分。候选人的教育目标是1)发展先进研究方法的技能，并形成合作，使深入和高影响的翻译研究成为可能；2)了解卡介苗抗肿瘤活性背后的潜在免疫机制；3)将研究成果转化为临床实践，目标是为膀胱癌患者提供一种替代膀胱切除的方法。此外，在泰勒·库里尔博士和伊恩·汤普森博士的指导下，候选人将培养专业能力，包括撰写拨款、高效的实验室管理，以及对研究道德的更好理解。这项拟议的研究的目的是检验卡介苗免疫疗法潜在的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抑制剂雷帕霉素来增强抗原特异性免疫并改善卡介苗的抗肿瘤效果。按计划进行的工作为后续研究奠定了基础，以测试雷帕霉素/卡介苗策略的潜在机制，并利用在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疗效；2)BCG特异性免疫有助于BCG疗效；3)雷帕霉素提高BCG疗效并增强抗原特异性免疫。这一方法意义重大，因为它提出了一个新的概念，即膀胱癌细胞可以表达卡介苗抗原，使卡介苗特异性免疫能够杀死这些膀胱癌细胞。这一方法是创新的，因为该提案是对目前癌症mTOR抑制模式的转变，目前的重点一直是直接抗肿瘤作用。

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.