We hypothesize that the activation and generation of tumor antigen- specific T cells will prevent tumor recurrence and metastasis. 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 cancer. This program proposes to extend the basic research and clinical observations from this group of investigators to explore the clinical use of immunotherapy RNA transfected DC and address the overall hypothesis, specifically to generate tumor antigen-specific T cells in patients with cancer, and to correlate the presence and magnitude of the induced T cell response (an immunologic endpoint) with the prevention of tumor recurrence and metastasis (a clinical endpoint). The proposed program seeks to coordinate three projects and three cores utilizing this novel and highly potent strategy, vaccination with DC transfected with RNA encoding either defined or undefined tumor antigens to induce tumor antigen- specific immune responses. An ongoing phase I clinical trial of active immunotherapy with DC transfected with RNA encoding a widely expressed tumor antigen, carcinoembryonic antigen (CEA), has demonstrated the safety and feasibility of this approach in patients with advanced disease. Analysis of patients following immunization demonstrates induction of CEA-specific T cells, and clinical responses in patients who mounted an immune response. To extend the potential of this strategy we propose clinical trials of RNA transfected DC to immunize colon and breast cancer patients with minimal tumor burden, but at high risk of recurrence. In addition, to avoid the potential pitfalls of targeting any single defined tumor antigen, we propose immunizing patients using total repertoire of tumor antigens and will not require prior determination or knowledge of the antigenic profile of each patient. Importantly, since mRNA content of a single tumor cell can be isolated and amplified, this strategy will not be limited by the availability of sufficient tumor tissue from patients for antigen preparations. The proposed program project will set the stage of 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.
Showing the most recent 10 out of 49 publications
