Improving immunotherapy in bladder cancer by targeting immune dysfunction

通过针对免疫功能障碍改善膀胱癌的免疫治疗

• 批准号: 8700763
• 负责人: Robert Scott Svatek
• 金额: $ 16.85万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700763
• 关键词: Address; Antigens; Aptitude; Attenuated; Autologous; Award; Bacillus (bacterium); Basic Science; Bladder; Bladder Neoplasm; Blood Cells; Cancer Immunology Science; Cancer Vaccines; Catheters; Clinical; Clinical Trials; Collaborations; Dendritic Cells; Development Plans; Diagnosis; Ethics; Excision; FDA approved; Follow-Up Studies; Funding; Genus Mycobacterium; Goals; Gold; Grant; Health; Human; Immune; Immune System Diseases; Immunity; Immunologics; Immunotherapy; Laboratories; Life; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Mentors; Mentorship; Methods; Modeling; Monitor; Mus; Mycobacterium Infections; Outcome; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Physicians; Procedures; Public Health; Relapse; Research; Research Methodology; Resistance; Scientist; Signal Transduction; Sirolimus; Staging; T-Lymphocyte; Testing; Therapeutic; Translating; Tumor Antigens; Tumor Immunity; Urethra; Vaccination; Vaccines; Work; Writing; cancer cell; cancer immunotherapy; career; career development; clinical efficacy; clinical practice; combat; design; efficacy trial; experience; human FRAP1 protein; improved; in vitro testing; innovation; insight; killings; mTOR Inhibitor; mTOR inhibition; monocyte; mouse model; neoplastic cell; novel; novel strategies; patient oriented research; prevent; response; skills; subcutaneous; translational study; treatment effect; tumor; tumor growth

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.

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中取得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，以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) 将研究结果转化为临床实践，目标是为膀胱癌患者提供膀胱切除的替代方案。此外，在博士的指导下。泰勒·库里尔（Tyler Curiel）和伊恩·汤普森（Ian Thompson），候选人将培养专业能力，包括资助写作、高效的实验室管理以及对研究伦理的更好理解。拟议研究的目的是检查 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。提出了一种使用 mTOR 抑制剂雷帕霉素来增强抗原特异性免疫并提高 BCG 抗肿瘤效果的新策略。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，并利用获奖期间开发的方法和经验进行 I/II 期疗效试验。将测试三个假设：1）肿瘤特异性免疫有助于卡介苗疗效； 2) BCG特异性免疫有助于BCG疗效； 3）雷帕霉素提高卡介苗疗效，增强抗原特异性免疫。该方法意义重大，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。该方法具有创新性，因为该提案是对当前癌症 mTOR 抑制范式的转变，目前的重点是直接抗肿瘤作用。