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

针对肾细胞癌中碳酸酐酶 IX 的热休克蛋白疫苗

• 批准号: 8045311
• 负责人: HYUNG L KIM
• 金额: $ 7.32万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-17 至 2012-03-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8045311
• 关键词: Animal Model; Animals; Antigen Targeting; Antigens; Antitumor Response; Basic Science; Binding; Biological Assay; CD8B1 gene; California; Cancer Vaccines; Cells; Cessation of life; Chicago; Clear Cell; Clinical Management; Clinical Trials; Complex; Diagnosis; Disease; Disease remission; Dose; Enzyme-Linked Immunosorbent Assay; Exhibits; Fellowship; Heat shock proteins; Heat-Shock Response; Histologic; Human; Hypoxia; Immune; Immune response; Immune system; Immunity; Immunization; Immunologic Adjuvants; Immunology; Immunotherapy; In Vitro; Incidence; Interferon-alpha; Interleukin-2; Kidney Neoplasms; Laboratories; Length; Los Angeles; Lymphocyte; Malignant Neoplasms; Mentors; Mentorship; Metastatic Renal Cell Cancer; Modeling; Molecular; Molecular Chaperones; Mus; Nature; Newly Diagnosed; Operative Surgical Procedures; Patients; Peptides; Peripheral Blood Lymphocyte; Phase; Phase I Clinical Trials; Population; Prevention; Primary Neoplasm; Program Development; Proteins; Radiation; Recombinants; Renal Cell Carcinoma; Renal carcinoma; Research; Research Personnel; Research Training; Residencies; Resistance; Students; T-Lymphocyte; Testing; Training; Training Programs; Translating; Translational Research; Tumor Antigens; Universities; Urologic Oncology; Urology; VHL mutation; Vaccines; Variant; base; carbonate dehydratase; career; chemotherapy; clinical practice; crosslink; cytokine therapy; cytotoxic; enzyme linked immunospot assay; experience; kidney cell; minimally invasive; monocyte; new therapeutic target; novel; novel therapeutics; novel vaccines; peripheral blood; prevent; professor; programs; protein complex; protein folding; response; treatment strategy; tumor; urologic; vaccine efficacy

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.

描述（由申请人提供）：本申请提出了一个为期5年的转化研究培训计划，用于发展泌尿肿瘤学的学术生涯。申请人在芝加哥大学完成了泌尿外科住院医师培训，并在洛杉矶的加州大学获得了泌尿肿瘤学和微创外科的奖学金。该计划提供将基本科学概念转化为新的治疗策略的培训。具体来说，一种基于热休克蛋白的疫苗靶向肾癌抗原，由潜在的VHL突变引起，是在热休克蛋白领域公认的领导者John Subjeck博士的指导下开发的。Subjeck博士指导过许多研究生、研究生和几位初级临床医生。该项目的共同导师包括免疫学教授Elizabeth Repasky博士和泌尿肿瘤学教授James Mohler博士，他们在成功的泌尿学学术生涯中结合了转化研究和临床实践。热休克蛋白（HSP）是一种有效的免疫激活剂。导师的实验室首次证明了利用热休克蛋白的天然伴侣功能结合肿瘤抗原并产生抗肿瘤免疫反应的可行性。这项研究的主要假设是，在体外与肾癌蛋白复合的热休克蛋白将作为肾癌的有效疫苗。具体目标是：1）确定HSP和肿瘤抗原的热休克复合物是否防止肿瘤形成（预防研究）和治疗已建立的肿瘤2）确定与肿瘤抗原复合的HSP是否刺激人外周血单核细胞并产生抗原特异性细胞毒性淋巴细胞（CTL）应答; 3）在晚期透明细胞RCC患者中使用与肿瘤抗原复合的HSP作为肿瘤疫苗进行I期临床试验。目前可用于转移性肾癌的疗法产生15- 20%的适度响应率。在理解疾病的分子机制方面的进展揭示了新的治疗靶点。提出了一种新的靶向肾肿瘤特异性抗原的免疫疗法。