GLYCOLIPID AND PROTEIN VACCINES AGAINST CANCER

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We have identified differentiation abundantly expressed on human cancers, minimally expressed on normal, tissues and immunogenic in cancer patients. These divide into three broad groups: small integral cell membra vgvvne glycolipids (gangliosides GMS2, GD2 and GD3), melanosomal glycoproteins (tyrosine, TRP2, gp75, gp100) and large cell surface mucines (MUC1). Vaccines against these antigens have been or will be constructed, tested and refined in the adjuvant setting, guided by in vitro assays to quantitate immunogenicity. Ganglioside vaccines perfected previously under this Program Project are most advanced. Antibodies induced by these vaccines react with the same gangliosides expressed on tumor cells in all (GM2) or most (GD2 and GD3) cases. MUC1 peptide vaccines have failed to induce high titers of antibodies or significant levels of T-cell immunity against MUC1 expressed at the tumor cell surface. The optical approach for inducing antibody, or helper or cytotoxic T-cell responses against the melanosomal glycoproteins remains unproven. The use of CTL defined peptides incorporated into heat shock proteins and proteins modified (xenogenized) in various ways are two approaches that have proven particular potent in preclinical models. Our specific aims are: I. Conduct a randomized adjuvant trial in melanoma patients using a trivalent KLH conjugate vaccine (containing GM2, GD2 and GD3 lactone) versus a monovalent KLH conjugate vaccine (containing GM2). II. Determine whether MUC1 peptide glycosylated at 1, 3, or 5 sites per tandem repeat inducers a more relevant response than the unglycosylated peptide in patients with resected breast cancer. III. Compare the CTL induction of heat shock protein 70 (hsp70) with that of previously tested adjuvants using the HLA A2 restricted CTL epitopes of tyrosinase: 368-377 (370D) and gp100: 209-217 (210M) as antigens. IV. Compare antibody, CD4 and CD8 responses after immunization with vaccines containing human, DNFB haptenized human or murine melanosomal proteins (tyrosinase, TRP2, gp75, gp100) of baculovirus origin.