Her-2/new (H2N) oncoprotein is overexpressed in 20-40% of patients with breast cancer. Recent studies from the applicant's laboratory have demonstrated that many patients with breast cancer have immunity to H2N with detectable levels of antibodies and CD4+ helper/inducer T cells directed against the H2N protein. Although the immune response was substantial, these patients had no clinical evidence of autoimmunity. In addition, the applicant has shown that H2N peptide-specific CTL can be generated by in vitro priming. Combined with the results of others demonstrating that TIL cells in a patient with ovarian cancer recognize a H2N peptide, these studies confirm that recognition of the H2N protein is within the realm of the T cell repertoire and importantly that H2N protein is processed in the class I antigen processing pathway. These investigations show that the H2N oncoprotein can elicit T cell responses and serve as a specific tumor antigen. Current research in the applicant's laboratory is centered around the development of H2N-specific adoptive T cell therapy and vaccine strategies for the treatment of breast cancer. Given that some patients with H2N-positive cancers have existent T cell responses to H2N, it should be possible to boost those responses. Although the patients with detectable immunity to H2N have no obvious autoimmunity, her concern is that augmentation of the immune response to this self protein may generate autoimmunity. Prior to initiation of clinical studies of H2N directed immunotherapeutics in breast cancer patients, the applicant thinks it is mandatory to evaluate the effects of inducing and boosting immunity to H2N in a rodent model. This application outlines the preclinical evaluation of immunity to the H2N protein using the rat to assess the effect of both vaccination and adoptive T cell therapy. These studies should be directly applicable to humans as the structure, function, expression and distribution of H2N is homologous in rats and humans.
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