This aim of this project is to develop a colorectal cancer vaccine using gene therapeutic methods of modifying dendritic cells. The goal will be to develop a dendritic cell-based vaccine in order to elicit a humoral and cell-mediated cytotoxic response against carcinoembryonic antigen (CEA) expressing tumor cells. Dendritic cells have been shown to be very potent antigen-presenting cells and can sensitize CD4+ and CD8+T cells in vitro. These cells are now being used in the immunotherapy of human non-Hodgkin's lymphoma, myeloma, and prostate cancer. This project will use recombinant adeno-associated virus (AAV) or feline immunodeficiency virus (FIV) to deliver the CEA gene to murine dendritic cells in vitro. CEA specific murine T cell proliferative and cytolytic responses will be studied in vitro. These gene modified dendritic cells will be used to generate an immune response in mice containing CEA expressing tumors. Both humoral and lymphoproliferative responses will be studied in vivo after vaccination of CEA-transgenic mice with the CEA-dendritic cell vaccine. Toxicity to endogenous tissues will be evaluated by pathologic examination. If an immune response can be elicited, then the vaccine will be used to protect mice against growth of CEA expressing tumors. The vaccine will also be tested in mice with established CEA expressing tumors. If the CEA gene modified dendritic cell vaccine can elicit a significant anti- tumor response without toxicity to normal tissues, then this would form the basis for a clinical trial in colorectal cancer patients harboring metastatic disease.
