Breast cancer is the most common malignancy in women and the incidence for developing breast cancer is on the rise. One in nine American women is destined to develop breast cancer in her lifetime. The HER-2/neu (H2N) oncogene and its protein product, pl85 H2N are associated with 20-40% of breast cancers. The presence of the protein is linked with more aggressive disease, is an independent predictor of poor prognosis in subsets of patients, and may play a role in the early stages of malignant transformation. These factors led to the initiation of studies examining H2N as a potential target for immunotherapy. Little work has been done to determine whether overexpressed, oncoproteins can be developed as targets for T cell therapy. The assumption has been that individuals would be immunologically tolerant or if immunity could be generated, it would be destructive to normal tissue. Preliminary data shows that some patients with breast cancer are immune to H2N and the responses are consistent with a primed response. Additional studies show cytotoxic T lymphocytes (CTL), specific for H2N peptides can be generated from primary in vitro immunization and in initial studies, can lyse H2N expressing tumor. The identification of primed responses to the H2N protein in breast cancer patients allows us to examine changes in immunity with disease progression and remission. Methods to elicit CTL responses should provide a means to determine whether patients with breast cancer have existent CTL responses and whether that CTL can lyse tumor for eventual use in treatment. The H2N protein is an appealing target for immunotherapy. It is present in the cytosol and at the cell surface available for processing by class I and II pathways, it contains multiple epitopes appropriate for binding MHC and potentially recognizable by all patients, and it is overexpressed; therefore, T cell therapies might be effective with minimal toxicity. The current proposal means to elucidate the biology and extent of the immune response of premenopausal patients with breast cancer to H2N protein in an effort to lay the foundation for development of immunotherapies in breast cancer centering around H2N as a target tumor antigen.
The specific aims of the current proposal are: (1) To examine CD4+ helper/inducer T cell responses to H2N protein in patients with H2N- positive cancers and detectable CD4+ T cell immunity to H2N:; (2) To examine CD4+ helper/inducer T cell responses to H2N protein in patients with H2N-positive cancers and no detectable CD4+ T cell immunity to H2N; (3) To examine CD4+ helper/inducer T cell responses to H2N protein in patients with H2N-negative cancers but detectable CD4+ T cell immunity to H2N; (4) To examine CD8+ cytolytic T cell responses to H2N protein identifying additional peptides capable of eliciting peptide-specific CTL, and determining if peptide-specific CTL can lyse breast cancer cells; (5) To determine whether CTL specific for H2N-positive breast cancer cells can be elicited from patients with breast cancer; and (6) To determine if H2N- specific CTL responses detectable in patients correlate with the presence of H2N-positive tumors, can lyse autologous H2N-positive tumors, and, if responses correlate with disease outcome.
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