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

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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.