Towards fully synthetic anticancer vaccines
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Cancer is a menacing, worldwide health problem for which there exist no effective therapies. In this thesis, an approach towards the development of novel fully synthetic carbohydrate-based cancer vaccines for the treatment of various human cancers is presented. Although several vaccines have a proven history in the fight against many serious diseases (such as polio, mumps, and measles), carbohydrate-based cancer vaccines are in their infancy and in the experimental stage. Three main obstacles inhibit the development of a carbohydrate-based cancer vaccine: the availability of pure oligosaccharides, the poor immunogenicity of pure oligosaccharides and T-cell independence of pure oligosaccharides. In this research, the three obstacles were eliminated through the convergence of three areas of scientific expertise: synthetic chemistry, vaccine formulation and immunology. To assess the cancer vaccine development, the Lewis antigen Ley was chosen as the carbohydrate tumor marker. The Lewis antigen Ley was chosen because it is overexpressed on the surface of cancer cells and has been previously identified as an important epitope for eliciting antibodies against colon and liver carcinomas. Large amounts of the tumor-associated Lewis antigen Ley were synthesized according to a new, highly efficient strategy and further used in the vaccine construction. Liposome was selected for vaccine formulation. A surface functionalized liposomal carrier system was constructed and optimized using a completely synthetic composition of adjuvants and lipomatrix. The obtained Lewis antigen, Ley, and the T-epitope peptide (QYI) were covalently coupled to the structurally-defined liposomal carrier system to afford a glycoconjugate vaccine. The efficacy of the novel therapeutic cancer vaccine was evaluated in an animal model, resulting in the stimulation of the desired immune response. In order to uncover the cross activity among the Lewis antigens, the dimeric tumor associated Lewis antigen Ley-Lex was also prepared following a similar strategy.