Preparation of Polyvalent Anticancer Vaccines for T-cell activation

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DESCRIPTION (provided by applicant): The discovery of a potent carbohydrate-based anticancer vaccine has been a long-standing goal for tumor immunologists. Its use harnesses the power of the human immune system to fight cancer. Such an approach is complementary to chemotherapy, and is especially promising for the treatment of cancer metastasis. By conducting the proposed research, we plan to develop a modified carbohydrate-based vaccine that will be able to induce a long-lasting immune system response to different types of cancer cells. We propose to achieve the superior immunogenic properties by modification of the currently available polyvalent anticancer vaccine that has been synthesized in Danishefsky's laboratories. The currently available polyvalent vaccine is only capable of B-lymphocyte activation. This activation results in a short- term immunogenic response; in order to induce a long-lasting immune response against the cancer cells, the activation of T-cell lymphocytes should be targeted. One of the reasons for the current vaccine's failure to interact with T-lymphocytes is its instability to cellular metabolism. We propose to increase the stability by modifying the glycosidic linkages holding carbohydrate units and attaching the carbohydrate epitopes to the vaccine backbone. It is known that the corresponding S-glycosides are more stable to enzymatic degradation as well as to the acidic medium inside lysosomes. Furthermore, S-glycosides have similar to O-glycosides conformational properties such that the immunogenicity of the vaccine is not significantly influenced by these modifications. We also propose to increase the affinity of the vaccine by incorporating a YAF peptide fragment to the vaccine backbone. Recently, it has been shown that the YAF peptide promotes delivery of carbohydrate epitope to a T-cell by binding to a MHC-II site. Thus, the objective of this proposal is to introduce S-glycosidic linkages and the YAF peptide into the currently existing polyvalent anticancer vacccine and to develop a consise chemical synthesis of the modified vaccine in order to deliver material for biological evaluation. We believe that the proposed work is very important for public health because every year cancer takes the lives of more than five hundred thousands Americans. The development of a potent anticancer vaccine would provide a new valuable tool to fight and prevent cancer using the power of human immune system.