Tumor progression is intimately associated with the appearance of unusual carbohydrates on the surface of cells. A broad and expanding body of preclinical and clinical studies demonstrates that naturally acquired, passively administered or actively induced antibodies against these carbohydrate-associated tumor antigens are able to eliminate tumor cells. Carbohydrate-based cancer vaccine developmenthas, however, been complicated by the difficulty of eliciting high titers of IgG antibodies in most patients. The successful development of a carbohydrate-based cancer vaccine requires a novel strategy for a more efficient presentation of tumor associated carbohydrate epitopes to the immune system resulting in a more efficient class switch to IgG antibodies. We have shown that a full-synthetic vaccine candidate composed of a tumor-associated carbohydrate-antigen, a promiscuous peptide T-helper epitope and the lipopeptide adjuvant S-[(R)-2,3- dipalmitoyloxy-propyl]-N-palmitoyl-(R)-cysteine (Pam3Cys) can successfully elicit high titers of IgG antibodies. The objective of this application is to investigate in detail the optimum architecture of a three- component cancer-vaccine for eliciting a strong and relevant anti-tumor immune response. Furthermore, the role of the TLR ligand (adjuvant) to polarize the immune response will be investigated. Thus, three- component cancer vaccines will be synthesized that differ in B- and T-epitopes, TLR ligands and topology The antigenicity of the synthetic compounds and ability of the antisera to recognize and neutralize cancer cells will be determined. Finally, the ability of the synthetic vaccine candidates to induce a range of cytokines relevant to adaptive immune response will be examined. At the completion of our studies, we will be able to make correlations between the architecture of the glycolipopeptides and innate and adaptive immune responses and the ability of antisera to recognize and eliminate cancer cells. These correlations will provide a firm scientific foundation for murine tumor-challenge studies or a phase I clinical trial.
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