Heat Shock Protein Vaccine Targeting Carbonic Anhydrase IX in Renal Cell Carcinom

描述(由申请者提供)：此申请建议一个为期5年的转化性研究培训计划，以发展在泌尿外科肿瘤学的学术生涯。申请者在芝加哥大学完成了泌尿外科住院医师资格，并在加州大学洛杉矶分校获得了泌尿外科肿瘤学和微创外科研究员学位。该计划提供将基础科学概念转化为新的治疗策略的培训。具体地说，一种针对肾癌抗原的以热休克蛋白为基础的疫苗是在约翰·塞贝克博士的指导下开发的，他是热休克蛋白领域公认的领导者。Subjeck博士曾指导过许多研究生、研究生和几名初级临床医生。该项目的共同导师包括免疫学教授伊丽莎白·雷帕斯基博士和泌尿外科肿瘤学教授詹姆斯·莫勒博士，他在成功的泌尿外科学术生涯中将翻译研究和临床实践结合在一起。热休克蛋白(HSPs)是一种有效的免疫激活剂。导师的实验室首先证明了利用热休克蛋白的天然陪伴功能结合肿瘤抗原并产生抗肿瘤免疫反应的可行性。这项拟议研究的主要假设是，在体外与肾癌蛋白络合的热休克蛋白将成为治疗肾癌的有效疫苗。具体目的是：1)在肾癌小鼠模型上确定热休克蛋白与肿瘤抗原的复合物是否能预防肿瘤形成(预防研究)和治疗已确定的肿瘤(治疗研究)，并将疫苗效力与其他基于热休克蛋白的疫苗策略进行比较；2)确定与肿瘤抗原复合的热休克蛋白是否能刺激人外周血单核细胞并产生抗原特异性的细胞毒性淋巴细胞(CTL)反应；3)在晚期透明细胞肾癌的患者中，使用HSP与肿瘤抗原复合的热休克蛋白作为肿瘤疫苗进行I期临床试验。目前可用的治疗转移性肾癌的方法产生了15%-20%的适度应答率。在了解该病潜在的分子机制方面的进展揭示了新的治疗靶点。提出了一种新的针对肾脏肿瘤特异性抗原的免疫治疗方法。

DESCRIPTION (provided by applicant): This application proposes a 5 year translational research training program for the development of an academic career in urologic oncology. The applicant completed urology residency at the University of Chicago and fellowships in urologic oncology and minimally invasive surgery at the University of California, Los Angeles. This program provides training for translating basic science concepts into novel therapeutic strategies. Specifically, a heat shock protein-based vaccine targeting a kidney cancer antigen, resulting from the underlying VHL mutation, is developed under the mentorship of Dr. John Subjeck, a well recognized leader in the field of heat shock proteins. Dr. Subjeck has mentored numerous graduate, postgraduate students, and several junior clinicians. Co-mentors for this project include Dr. Elizabeth Repasky, Professor of Immunology, and Dr. James Mohler, Professor of Urologic Oncology, who has combined translational research and clinical practice in a successful academic urology career. Heat shock proteins (HSPs) are potent immune activators. The mentor's laboratory first demonstrated the feasibility of using the natural chaperoning function of HSPs to bind tumor antigens and produce an antitumor immune response. The major hypothesis of the proposed research is that HSPs complexed in vitro to a kidney cancer protein will serve as an effective vaccine for kidney cancer. The specific aims are: 1) Determine if heat shock complexes of HSP and tumor antigen prevent tumor formation (prevention study) and treat established tumors (treatment study) in a murine model of renal cell carcinoma (RCC), and compare vaccine efficacy to other heat shock protein based vaccines strategies; 2) Determine if HSP complexed to tumor antigen stimulates human peripheral blood monocytes and generates antigen-specific cytotoxic lymphocyte (CTL) response; 3) Perform a phase I clinical trial using HSP complexed to tumor antigen as a tumor vaccine in patients with advanced, clear cell RCC. Currently available therapies for metastatic kidney cancer produce modest response rates of 15-20%. Advances in the understanding of the molecular mechanism underlying the disease have revealed new therapeutic targets. A novel, immunotherapy targeting a kidney tumor-specific antigen is proposed.