. Previous work has demonstrated that breast carcinoma is included among those tumors that induce T cell responses. Tumor-infiltrating lymphocytes (TIL) isolated from solid breast tumor or tumor-associated lymphocytes (TAL) isolated from metastatic effusions that were activated with solid-phase anti-CD3 antibody and repeatedly reactivated with autologous tumor cells showed potent anti-tumor cytolysis. This cytolytic activity was mediated through the T cell receptor on CD8+ cytotoxic T lymphocytes (CTL) that bound to antigenic peptides presented by HLA-A2 molecules expressed on the tumor cells. HLA- A2+ CTL crossreacted with most HLA-A2+ allogeneic breast tumor cells and HLA-A2+ ovarian tumor cells indicating the presence of shared antigens. Recent progress in the understanding of antigen presentation and structural analysis has elucidated the requirements for peptides to bind to HLA-A2 molecules. Two tumor-associated antigens (TAA) have been identified in breast cancer that are associated with the induction of CTL responses, the protooncogene HER2/neu and the mucin core protein. Both proteins are expressed on most if not all epithelial-derived tumors such as breast carcinoma and ovarian carcinoma. It is, therefore, likely that both proteins are also endogenously processed and expressed on the cell surface by HLA class I molecules which could explain the crossreactivity of tumor-specific T cells. In the case of HER2/neu, synthetic peptides derived from the HER2/neu peptide sequence have confirmed that at least one such peptide presented by HLA-A2 induces lytic activity in tumor- specific CTL derived from breast, ovarian and lung carcinoma. In addition, HLA-A2+ breast or ovarian TIL/TAL repeatedly stimulated in vitro with this HER2/neu-derived peptide induced CTL not only against peptide-pulsed B cells, but also against autologous tumor cells. The applicant has isolated peptides from ovarian tumor cell surface HLA molecules by mild acid washes and fractionation of those peptides by reverse-phase HPLC. Several individual peptide fractions were found to induce lytic activity in tumor-specific CTL from breast or ovarian cancer. Sequencing of those peptide fractions might identify the gene(s) that code for these antigens. First, the identification of TAA permits the screening of any human tumor sample for the presence of these antigens. Second, TIL or TAL isolated from breast cancer patients could be expanded in vitro in the presence of purified synthetic tumor-derived peptides to preferentially expand tumor-specific CTL. These CTL could be used in adoptive immunotherapy of cancer patients. Finally, synthetic tumor-derived peptides could be used in a vaccine-based treatment of patients with cancer.
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