This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Epithelial ovarian cancer is the fourth most lethal of all female cancers; it is the most lethal of all gynecologic neoplasms, and accounts for more deaths each year than all other gynecologic neoplasms combined (American Cancer Society Cancer Statistics 2000, Jan, Vol. 50, No.1). Given the relatively asymptomatic nature of early stage disease and the absence of any effective screening modalities for its early detection, seventy-five percent of patients diagnosed with epithelial ovarian cancer will have advanced stage disease at the time of their diagnosis. Surgery is the initial mainstay in terms of treatment for this disease, with optimal cytoreduction the goal of initial surgical debulking. Unfortunately, only approximately 40% of women can be successfully cytoreduced to minimal volume disease prior to the initiation of cytotoxic chemotherapy. Approximately 70-80% of women will respond to chemotherapeutic regimens, with 30-50% achieving a complete clinical response. The response is rarely a lasting one, however, and the disease will typically recur within 3-5 years, with patients ultimately succumbing to the disease soon thereafter. The five-year survival rate for women with advanced stage ovarian carcinoma is approximately 21%. The overall cure rate for such advanced stage disease is virtually zero. Immunotherapeutic approaches would offer a potentially useful treatment for ovarian cancer patients based on the following immunologic criteria. First, ovarian tumors express MHC class I molecules allowing for their recognition by CD8+ T lymphocytes. Second, ovarian tumors express mutated versions of proteins associated with cellular proliferation such as p53, elevated levels of aberrantly glycosylated proteins such as MUC-1, and elevated levels of non-mutated proteins such as folate binding protein, Her-2/neu, MAGE-1, or NY-ESO-1, which could serve as targets for cellular and humoral immune responses. Indeed, tumor infiltrating lymphocytes and antibodies specific for these tumor antigens have been isolated from ovarian cancer patients. More importantly, recent studies have identified antigenic fragments from these proteins that are capable of stimulating immunological responses and can be incorporated in novel vaccine designs.The goal of the proposed study is to acquire preliminary information on the immunogenicity of a vaccine comprising class I MHC-restricted synthetic peptides derived from shared ovarian cancer-associated proteins (MAGE-A1, Her-2/neu, and folate binding protein (FBP)) administered in conjunction with a class II MHC-restricted helper synthetic peptide derived from the tetanus toxoid protein. There are several advantages associated with the development of the proposed peptide-based vaccine. First, the ovarian cancer-associated proteins to be used in this study are usually encoded by non-mutated genes, which lack tumor-specific mutations. Therefore, epitopes derived from these molecules could be useful in a vaccine for a large population of ovarian cancer patients. Second, as we are vaccinating with defined ovarian cancer-associated epitopes as opposed to a whole cell vaccine, immunological responses to the vaccinating peptides can be easily monitored. Third, micrometastases may be made up of a heterogenous population of cells, which express a different profile of tumor-associated antigens. Thus, vaccines incorporating a single ovarian cancer-associated epitope may be inadequate in generating a complete immune response against residual tumor. Ideally, a polyvalent vaccine incorporating epitopes derived from multiple antigens should compensate for the differential display tumor-associated antigens.The following study is unique among ovarian vaccine trials proposed to date in that the described vaccine incorporates five epitopes derived from three different ovarian cancer-associated proteins (MAGE-A1, Her-2/neu, and FBP). The epitopes were chosen based on their MHC restriction and the frequency of expression of the parent protein in ovarian cancer. The goals of the proposed study are to assess the immunogenicity of a vaccine comprising ovarian cancer-associated peptides in adjuvant.
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