Project #1 of the program will focus on performing clinical trials of RNA transfected dendritic cell (DC) immunotherapy. The overall objective will be to develop a clinically relevant vaccine strategy for the treatment of minimal residual metastatic cancer. We proposed first define the role of RNA transfected DC in inducing cytotoxic T lymphocytes (CTL) and T helper (Th) cells using a defined tumor antigen, carcinoembryonic antigen (CEA). We are currently conducting a phase I clinical trial of active immunotherapy using DCs transfected with CEA RNA which demonstrates the safety and feasibility of this approach in patients with advanced metastatic disease. In addition, 6 out of 10 treated and evaluated patients have demonstrable CEA-specific immune responses, including two patients with objective clinical responses. We hypothesize that the magnitude and clinical relevance of a CEA-specific T cell response will be optimal in a setting of minimal tumor burden. As a logical extension of this phase I study, the primary objective of project #1 is to perform clinical trials of RNA transfected DC immunotherapy. We propose an immunological II study to determine whether vaccination with CEA RNA transfected DC is capable of eliciting CEA-specific CD4+ and CD8+ T cell responses in CEA positive colorectal cancer patients in a minimal disease setting.
The specific aims reflect a logical progression of studies necessary to determine the role of RNA transfected DC as a widely applicable platform for presenting tumor rejection antigens to elicit tumor specific immunity, and to determine if measurable immunologic responses will correlate with clinical responses. In addition, a major hypothesis to be tested is that antigen encoded by tumor represents a more authentic source of tumor rejection antigen than any single antigen. Using information from preclinical studies performed in Project #2, we propose a phase I clinical trial of active immunotherapy of patients with metastatic CEA expressing cancer using autologous DC transfected with autologous total tumor RNA.
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