DEVELOPMENT OF CANCER VACCINES

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We have identified a series of differentiation antigens which are amply expressed on human cancers, have limited expression on normal tissues and are known to be potentially immunogenic in the cancer bearing host. These antigens can be separated into three quite separate categories: Small integral cell membrane antigens (gangliosides such as GM2, GD2 and GD3 lactone), intracellular glycoproteins and proteins (tyrosinase and MAGE-1) and large cell surface mucins which are also shed into the extracellular space (MUC-1, TF and sTn). Vaccines against these antigens will be constructed, tested and refined in the adjuvant setting, guided by in vitro assays to quantitate immunogenicity. Because of the location and chemical nature of these antigens, the immune responses expected are quite different. We will assay serological responses against ganglioside, TF and sTn antigens, and will follow serologic, T cell proliferative responses and cytotoxic T cell responses against the other antigens. Three basic approaches to augmenting the immunogenicity of these antigens will be used: mixture with the immunological adjuvant QS-21, conjugation to immunogenic carrier proteins such as keyhole limpet hemocyanin (KLH) or expression in recombinant vectors such as BCG. A series of step by step small clinical trials will be conducted with vaccine immunogenicity defined by serological and cell mediated immune responses. In Aim 1, patients with melanoma and sarcoma will be immunized against GM2, GD2 and GD3 lactone by KLH conjugate vaccines plus QS-21. In Aim 2, the feasibility of inducing an immune response against tyrosinase and MAGE-1 will be studied in melanoma patients vaccinated with these proteins or peptides plus QS-21, or KLH conjugates of these proteins or their immunogenic peptide epitopes. Knowledge of the amino acid sequence of peptide epitopes on tyrosinase and MAGE-1 presented by particular HLA antigens permits precise determination of the cytotoxic T cell response against these peptides and will presumably reflect the optimal immunization approach to other not yet identified peptides on these proteins. In Aim 3, MUC-1, TF and sTn-KLH conjugate preparations, as well as recombinant BCG expressing MUC-1 as a consequence of gene transduction, will be used to induce immune responses against this dominant breast cancer mucin, in breast cancer patients who are free of detectable disease and subsequently in breast cancer patients with elevated tumor markers. It is the goal of each Aim to optimize the vaccines and provide preliminary evidence which may be the basis for subsequent multicenter Phase III trials.