The overall hypothesis of this proposal is that the activation of tumor antigen specific T cells will prevent tumor recurrence and metastasis. The frequency of cytotoxic T cells circulating in the peripheral blood of patients with metastatic renal cell carcinoma (RCC) and directed against RCC associated antigens is low or undetectable. In this proposal, we hypothesize that administration of escalating doses of tumor RNA transfected DC to patients with metastatic RCC will lead to detectable levels of circulating, functionally active tumor specific T cells. We have developed a novel, broadly applicable, and clinically feasible immunization strategy, using dendritic cells (DC) transfected with RNA encoding tumor antigens to elicit significant levels of tumor antigen specific T cells in patients with RCC. This program proposes to extend the basic research and clinical observations from this group of investigators to explore the clinical use of immunotherapy with tumor RNA transfected DC and address the overall hypothesis, specifically to generate and characterize tumor antigen specific T cells in patients with cancer. An ongoing phase I clinical trial of active immunotherapy with DC transfected with RNA encoding a widely expressed tumor antigen, prostate specific antigen (PSA), has demonstrated the safety and feasibility of this approach in patients with advanced prostate carcinoma. Preliminary analysis of patients following immunization demonstrates the induction of PSA specific T cells, suggesting the bioactivity of this vaccine strategy. To broaden the potential of this strategy and to avoid the potential pitfalls of targeting any single defined tumor antigen, we propose immunizing patients using total: tumor derived RNA transfected DC which we have demonstrated to elicit immune responses against a broad repertoire of tumor antigens and will not require prior determination or knowledge of the antigenic profile of each patient. The proposed program will set the stage for definitive trials designed to demonstrate a clinical benefit of inducing tumor antigen specific T cells in cancer patients using RNA transfected DC vaccines to reduce cancer recurrence and metastasis.
| Vieweg, Johannes; Dannull, Jens (2005) Technology Insight: vaccine therapy for prostate cancer. Nat Clin Pract Urol 2:44-51 |
| Vieweg, Johannes; Jackson, Andrew (2005) Modulation of antitumor responses by dendritic cells. Springer Semin Immunopathol 26:329-41 |
| Su, Zhen; Dannull, Jens; Heiser, Axel et al. (2003) Immunological and clinical responses in metastatic renal cancer patients vaccinated with tumor RNA-transfected dendritic cells. Cancer Res 63:2127-33 |
