CONSTRUCTION OF VACCINES AGAINST BREAST CANCER

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The overall goals of this proposal are to identify antigenic epitopes on breast cancer which are immunogenic to the human immune system, determine the optimal method of benefit which may be the basis for a Phase III vaccination trial. Two breast cancer cell lines, selected for high expression of Lewis(y), Lewis(X), Tf, sTn, MUC-1, CEA, HER2/neu, ras and mutant p53, will be used as immunogen. Their immunogenicity will be boosted by immunological adjuvant QS21 and transduction of genes for IL2 and interferon gamma. Immunogenicity of these antigens will be detected initially by standard tests for antibody, delayed type hypersensitivity and proliferative T cell responses against each of these antigens, and HLA unrestricted cytotoxic T cell responses against MUC-1. The sensitivity of detection will be further increased by establishment of human monoclonal antibodies and by in vitro sensitization and cloning of antigen specific T cell lines. Purified and/or synthetic versions of most of these antigens as well as a panel of typing cell lines are available for these assays. Once antigens are identified as potentially immunogenic (and the immunogenic epitopes determined) keyhole limpet hemocyanin (KLH) conjugate vaccines will be prepared and tested in the clinic. Since three breast cancer antigens are already known to be potentially immunogenic in man (Tf, sTn and MUC-1) these will be used in the initial KLH conjugate vaccine trials. Our specific aims are: 1. Compare the immunogenicity of tumor antigens expressed on breast cancer cell lines SKBR3 and MCF7 which have been irradiated and mixed with immunological adjuvant QS21, which have been transduced with the IL2 and interferon gamma genes, or which have been transduced with these cytokine genes and mixed with QS21. 2. Determine the optimal synthetic epitopes and conjugate preparations for induction of antibody and T cell responses against immunogenic breast cancer antigens as they are identified. Initially this will include Tf, sTn and MUC-1 antigens. 3. Compare the immunogenicity of breast cancer antigens expressed on the optimal whole cell vaccine identified in Aim I with the immunogenicity of these same antigens expressed in the optimal synthetic conjugate vaccines identified in Aim 2. 4. Conduct a Phase II trial with the most immunogenic vaccine combination in 30 patients with breast cancer who are free of detectable disease but have elevated circulating tumor markers.