Synthesis and immunological evaluation of a three-component cancer vaccine candidate
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Cancer is an invincible menace that contributes to about 7 million deaths annually, or 12.5% of total annual deaths worldwide. However, advances in surgery, chemotherapy and radiation therapy have reduced mortality rates. In this thesis, a novel approach towards the development of a fully synthetic carbohydrate-based cancer vaccine for various forms of human cancers is presented which contains all the necessary components required for cancer immunotherapy. Although the idea of vaccination on a mass scale is more than 200 years old, carbohydrate-based cancer vaccines are still in a developmental and experimental stage. Carbohydrate-based cancer vaccine development has been complicated by the difficulty of eliciting high titers of IgG antibodies in patients. It appears that the induction of IgG antibodies against a tumor-associated carbohydrate is much more difficult than the induction of similar antibodies against viral and bacterial carbohydrates because carbohydrates are auto-antigens and well tolerated by the immune system. Also, carbohydrates are poor immunogens. Some of the obstacles that inhibit the development of a carbohydrate-based cancer vaccine are the availability of pure oligosaccharides, and poor immunogenicity of oligosaccharides. In this research, we have developed a three-component vaccine candidate composed of a tumor-associated antigen, a promiscuous peptide T-helper epitope and a lipopeptide adjuvant. A three-component vaccine has a number of distinctive advantages over a traditional conjugate vaccine. For example, the minimal subunit vaccine does not suffer from epitope suppression, which is a characteristic of carbohydrate-protein conjugates. Apart from providing danger signals, lipopeptide Pam3CysSK4 also facilitates the incorporation of the antigen into liposomes. Finally, a highly convergent method based on sequential native chemical ligation is developed, which allows the construction of three-component vaccine candidates in an efficient manner. This method also allows studying structure-activity relationship (SAR) studies for various components of the vaccine. Besides synthetic chemistry, the research focuses vaccine formulation and immunology.