The overall objective of this STTR program is to develop an effective cancer vaccine based on class II T cell epitopes derived from four tumor-associated antigens (TAAs) that are commonly over-expressed in ovary-and breast-derived tumors. The role of CD4+ T cell in eliciting an anti-tumor response is critical. The development of tumor specific CTL and the generation of immunologic memory is dependent on CD4+ T cells. Preclinical and clinical studies conducted by our University of Washington colleagues and others using T helper vaccines targeting a single TAA are encouraging, but the full immunological and clinical potential for vaccines comprised of multiple class II epitopes derived from multiple TAA remains to be investigated. In Phase I of the current proposal, well established Epimmune technologies and processes will be utilized to identify TAA-derived peptides that bind to multiple HLA-DR molecules. These HLA-DR supertype peptides will then be tested for immunogenicity in a human in vitro T cell assay utilizing patient PBMC. Peptides demonstrated to be human CD4+ T cell immunogens, as defined by induction of recall or primary T cell responses will be designated as candidates for use in the vaccine. From these novel epitopes we will define a multi-epitope clinical candidate vaccine based on overall population coverage and TAA coverage, preliminary characterization of physical/chemical properties of each peptide epitope and formulation studies on combinations of these peptides. A murine model of breast cancer will be utilized for preclinical testing of the novel epitopes and the immunogenicity of the vaccine formulation. For Phase II of this project, we will propose to 1) complete the pre-clinical development program required for IND submission and 2) conduct a Phase I clinical study evaluating safety and immunogenicity of the vaccine. The specific aims to be proposed for Phase II of this program will represent a subset of the development activities required to execute this plan. PROPOSED COMMERCIAL APPLICATIONS: Recurrence of disease following surgery, with or without adjuvant chemotherapy, remains a serious medical problem for ovarian and breast cancer patients. This vaccine is designed to induce T-cell responses directed against multiple TAA, in order to prevent or delay disease recurrence after optimal primary therapy.
Thesaurus Terms: breast neoplasm, neoplasm /cancer vaccine, ovary neoplasm, tumor antigen, vaccine development MHC class II antigen, T lymphocyte, cyclin, peptide, protein binding, protooncogene biotechnology, clinical research, enzyme linked immunosorbent assay, human subject, laboratory mouse, patient oriented research
