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师-科学家，积极致力于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实施方面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领域取得成功的必要组成部分。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，从而实现深入和高影响力的转化研究；2)了解卡介苗抗肿瘤活性的潜在免疫机制；3)将研究成果转化为临床实践，为膀胱癌患者提供一种替代膀胱切除术的方法。此外，在dr。泰勒·库里尔和伊恩·汤普森，候选人将培养专业能力，包括拨款写作，有效的实验室管理，以及对研究伦理的更好理解。本研究的目的是研究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卡介苗在膀胱癌中的临床活性。提出了一种利用mTOR抑制剂雷帕霉素增强抗原特异性免疫和改善卡介苗抗肿瘤作用的新策略。按计划开展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，并利用本奖项期间开发的方法和经验开展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卡介苗的疗效；2)卡介苗特异性免疫与卡介苗效力有关；3)雷帕霉素提高卡介苗疗效，增强抗原特异性免疫。该方法具有重要意义，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杀死这些膀胱癌细胞。该方法具有创新性，因为该提议是对目前癌症中mTOR抑制的范式的转变，目前的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.