Preparation of Polyvalent Anticancer Vaccines for T-cell activation

描述(申请人提供)：发现一种有效的基于碳水化合物的抗癌疫苗一直是肿瘤免疫学家的长期目标。它的使用利用了人类免疫系统的力量来抗击癌症。这种方法是对化疗的补充，在治疗癌症转移方面特别有希望。通过开展这项拟议的研究，我们计划开发一种基于碳水化合物的改良疫苗，该疫苗将能够对不同类型的癌细胞诱导持久的免疫系统反应。我们建议通过对目前在Danishefsky实验室合成的多价抗癌疫苗进行修改来获得更好的免疫原性。目前可用的多价疫苗只能激活B淋巴细胞。这种激活会导致短期的免疫原性反应；为了诱导对癌细胞的长期免疫反应，T细胞淋巴细胞的激活应该是靶点。目前疫苗未能与T淋巴细胞相互作用的原因之一是它对细胞代谢的不稳定。我们建议通过修饰含有碳水化合物单元的糖苷键和将碳水化合物表位连接到疫苗主干上来增加稳定性。已知相应的S糖苷对酶降解以及溶酶体内的酸性介质更稳定。此外，S糖苷具有与O糖苷相似的构象性质，因此疫苗的免疫原性不会受到这些修饰的显著影响。我们还建议通过在疫苗骨架上掺入YAF多肽片段来增加疫苗的亲和力。最近，有研究表明，YAF多肽通过与MHC-II结合促进碳水化合物表位向T细胞的递送。因此，本研究的目的是在现有的多价抗癌疫苗中引入S-糖苷键和YAF多肽，并开发一种修饰疫苗的化学合成方法，以便为生物学评价提供材料。我们认为，这项拟议的工作对公共卫生非常重要，因为每年有50多万美国人死于癌症。一种有效的抗癌疫苗的开发将为利用人类免疫系统的力量抗击和预防癌症提供新的有价值的工具。

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.