Increasing evidence supports the notion that all tumors posses tumor- specific antigens capable of being recognized by antigen-specific T cells. These tumor-specific neo-antigens are the consequence of either novel amino acid sequences generated by mutations or rearrangements. Alternatively, these antigens may derive from genes that are silent in normal cells but become activated in the tumor cell. Over the past 5 years, our laboratory has developed a novel strategy in various murine tumor models which results in the activation of tumor-specific T cells capable of generating systemic antitumor immunity. This approach involves immunization with tumor cells engineered by gene transfer to locally secrete cytokines which alter the way in which tumor antigens are presented to T cells in vivo. This proposal seeks to apply our gene targeted immunotherapy approach for the development of immunotherapy for human pancreatic and colorectal cancers. Specifically, we plan: 1) Develop methods to selectively expand fresh human pancreatic and colorectal cancer explants in vitro, for the development of a genetically altered cytokine-secreting tumor vaccine; 2) Develop methods to optimize cytokine gene transfer to primary human pancreatic and colorectal cancer cell populations; 3) Develop in vitro assays for detecting and evaluating specific, antitumor immune responses. We have recently developed this vaccine strategy for the treatment of patients with advanced renal cell carcinoma. But our murine data has revealed that these tumor vaccines are most effective at curing established, micro metastases, which is our best model for minimal residual disease. Patients with stage 2 or 3 pancreatic carcinoma and Duke's B2 or C colorectal carcinoma would therefore be ideal candidates for this vaccine strategy, if given in the adjuvant setting. Identification of immunologic assays that can predict immune responses generated by the tumor vaccines is critical for monitoring the treatment of patients with minimal residual pancreatic and colorectal carcinomas.
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