IMMUNITY TO HER-2/NEU PROTEIN IN BREAST CANCER

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The HER-2/neu proto-oncogene is amplified and overexpressed in 20-40% of invasive breast cancers. HER-2/neu overexpression is associated with aggressive disease and is an independent predictor of poor prognosis in several subsets of patients. HER-2/neu may also be related to cancer formation, with overexpression being detectable in 50-60% of ductal carcinomas in situ. The overall goal for our laboratory has been to develop specific T cell therapy directed against proteins involved in malignant transformation. We have begun to examine immunity to HER-2/neu protein in breast cancer patients. Our preliminary studies have discovered that some patients with breast cancer have existent CD4+ helper/inducer T cell immunity and antibody-mediated immunity to HER-2/neu protein. It has been assumed that normal individuals would be immunologically tolerant to overexpressed oncogenic proteins and that immunity could not be generated; however, if immunity could be generated, the result would be destructive autoimmunity. Preliminary data demonstrating that HER-2/neu-reactive T cells and antibody are already present in the peripheral blood of breast cancer patients implies that immunity to HER-2/neu is induced in some individuals with cancer by virtue of the presence of growing tumor expressing the antigen and gives credence to the concept that HER-2/neu- specific immunity can be used in therapy without destroying normal tissue. Detection of immunity to HER-2/neu might also provide a method for screening and early detection of breast cancer and changes in the level of immunity might correlate with disease state an predict relapses. Additional preliminary studies demonstrated that primary in vitro immunization with HER-2/neu peptide fragments can by used to elicit HER- 2/neu peptide-specific CD8+ cytotoxic T cells (CTL). Methods to elicit HER-2/neu peptide-specific CD8+ T cells should provide a means to determine whether patients with breast cancer have existent CTL responses to HER- 2/neu and may provide a means of generating CTL capable of lysing autologous cancer cells for eventual use in therapy. The overall goal of this proposal is to determine whether existent immunity to HER-2/neu protein has diagnostic an prognostic significance as well as to identify the patient subgroups which might respond to therapeutic intervention with HER-2/neu reactive T cells. The specific aims are: (10 to examine CD4+ helper/inducer T cell responses to HER-2/neu protein; (2) to examine CD8+ cytotoxic T cell responses to HER-2/neu protein; and (3) to examine antibody responses to HER-2/neu protein.