Pancreatic adenocarcinoma continues to be one of the most difficult cancers to treat; new therapies are urgently needed. Murine studies employing tumor cells genetically-modified to express cytokines have demonstrated the induction of potent T cell immunity that can cure mice of pre-established tumors. Although the specificity of the immune response seen in these models suggests that antigens expressed by the tumor are recognized by the ensuing immune response, in most cases the identity of these antigens is unknown. The identification of human melanoma antigens has validated these earlier hypotheses, and has provided a strong impetus for the identification of other human tumor antigens that can be exploited therapeutically. The most direct approach for antigen identification requires generating T cell clones to screen cDNA libraries or eluted HPLC fractions. These current antigen isolation methods are tedious and slow. The recent sequencing of the human genome provides a unique opportunity to more rapidly identify candidate pancreatic cancer antigens. Taking advantage of new RNA expression technologies like SAGE, our gene discovery colleagues in the SPORE program are rapidly developing a database of proteins that are differentially expressed by pancreatic tumors. Drawing on our previous experience with antigen identification, and utilizing materials from patients concurrently enrolled on a vaccine study, we will identify tumor antigens expressed by human pancreatic adenocarcinomas. Specifically, we will: 1) enroll patients into a phase II vaccine study comparing cytoreductive doses of Gemcitabine or immune modulating doses of Paclitaxel, plus vaccine, to assess patients for immune mediated vaccine responses; 2) perform in vivo and in vitro assays to measure post-vaccination systemic responses; 3) screen and characterize a growing panel of pancreatic cancer associated proteins for recognition by lymphocytes isolated from vaccinated patients who demonstrate immune responses in aims 1 and 2. Candidate antigens that are identified will be further analyzed for: recognition by pancreatic cancer-specific T clones that we have generated previously and for the ability to stimulate naive T cells isolated from unvaccinated patients. Ultimately, the identification of common pancreatic antigens will allow the development of generalized vaccine approaches that can induce immune responses potent enough to treat pancreatic adenocarcinoma.
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