Colorectal carcinoma represents 15% of all malignancies and is the second leading cause of cancer related deaths. In patients with metastatic disease, treatment is palliative and does not prolong survival. In this project we will develop a transfusion based immunotherapeutic approach to colorectal cancer that utilizes dendritic cells (DC) pulsed with carcinoembryonic antigen (CEA), a well characterized membrane glycoprotein overexpressed on the majority of gastrointestinal malignancies, including colorectal cancer. DC are extremely potent antigen presenting cells, capable of sensitizing naive T lymphocytes to protein antigens and eliciting immune responses, in vitro and in vivo. Our group has developed methods for obtaining DC from human peripheral blood and demonstrated that these cells, but not monocytes or B cells, can sensitize naive CD4+ and CD8+ T cells to nominal antigens, in vitro. Recently. in collaboration with Ronald Levy's laboratory we demonstrated in patients with malignant B cell lymphoma that infusion of immunoglobulin idiotype pulsed DC is well tolerated and induces antigen specific T cell responses and tumor regression. In the proposed studies DC expressing CEA determinants as a result of antigen pulsing or gene transfer will be evaluated for their immunogenicity and anti-tumor effects in an animal model of colorectal carcinoma and in patients with disseminated colorectal carcinoma.
Four specific aims are proposed: l) development of methods for introducing CEA into DC such that the antigen is processed and presented on the cell surface in association with MHC class I and II determinants, resulting in the induction of CEA-specific T cytolytic and proliferative responses; 2) evaluation and comparison of the immunogenicity of CEA-pulsed DC and DC expressing CEA determinants as a result of gene transfer, in vivo, in a mouse model of colorectal cancer; 3) evaluation of the anti-tumor effects of CEA-pulsed DC in this murine model; and 4) analysis of the immunogenicity, toxicity and anti- tumor effects of CEA pulsed DC in patients with disseminated colorectal carcinoma. The results of these studies should indicate whether transfusion based immunotherapy with DC combined with CEA has a potential role in the treatment of colorectal cancer.
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