Pancreatic adenocarcinoma continues to be one of the most difficult cancers to treat. New therapies are urgently needed for the majority of patients with this disease. Murine studies employing tumor cells genetically- modified to express cytokines have demonstrated the induction of potent immunity that can cure mice of preestablished tumors. Experiments aimed at dissecting the mechanism of this response have revealed that both CD8+ and CD4+ T cells are critical effectors of the systemic immunity generated. These studies have led to ongoing clinical trials that are testing this approach for the treatment of patients with cancer. Although the specificity of the immune response seen in these models suggests that unique antigens are being expressed by the tumor and recognized by the ensuing immune response, in most cases the identity of these antigens is unknown. Recently, the identification of several murine and 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. Antigen identification requires methods for generating T cell lines and clones, and for isolating either the gene encoding the tumor antigen or the antigen itself. We have developed methods for routinely generating tumor-specific CD8+ and CD4+ T cells from lymphocytes isolated from vaccinated patients. However, current antigen isolation technologies only allow the routine identification of Major Histocompatibility Complex (MHC) class I-restricted antigens. There is evidence to suggest that at least some MHC class I and II-restricted tumor- specific antigenic epitopes may derive from the same cellular protein. In addition, pre-clinical models evaluating recombinant antigen-specific vaccine strategies have demonstrated priming of potent antitumor immunity when the product of a gene encoding for a single tumor-specific antigen is delivered to both the MHC class I and II antigen-processing pathways. Drawing on our previous experience with antigen identification, we will identify tumor antigens expressed by human pancreatic adenocarcinomas. Both CD8+ and CD4+ pancreatic tumor-specific T cell lines and clones will be generated from lymphocytes isolated from patients with adenocarcinoma of the pancreas following vaccination with a GM-CSF secreting pancreatic tumor vaccine. A genetic approach will be used to identify genes encoding for MHC class I-restricted antigens. The identified antigens will be evaluated for recognition by CD4+ T cell lines and clones. Ultimately, the identification of common pancreatic antigens will allow the development of generalized gene therapy vaccine approaches that can generate immune responses potent enough to treat adenocarcinoma of the pancreas.
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