Preparation of Polyvalent Anticancer Vaccines for T-cell activation

描述（由申请人提供）：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对抗癌症。这种方法是对化疗的补充，并且特别有希望用于治疗癌症转移。通过进行拟议的研究，我们计划开发一种基于碳水化合物的改良疫苗，该疫苗将能够诱导对不同类型癌细胞的持久免疫系统反应。我们建议通过修改Danishefsky实验室合成的现有多价抗癌疫苗来实现上级免疫原性。目前可用的多价疫苗仅能够激活B淋巴细胞。这种活化导致短期免疫原性应答;为了诱导针对癌细胞的持久免疫应答，应当靶向T细胞淋巴细胞的活化。目前的疫苗不能与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性。我们建议通过修饰保持碳水化合物单元的糖苷键并将碳水化合物表位连接到疫苗骨架来增加稳定性。已知相应的S-糖苷对酶促降解以及对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，使得疫苗的免疫原性不受这些修饰的显著影响。我们还提出通过将YAF肽片段并入疫苗骨架来增加疫苗的亲和力。最近，已经显示YAF肽通过结合MHC-II位点促进碳水化合物表位递送至T细胞。因此，本提案的目的是将S-糖苷键和YAF肽引入到目前存在的多价抗癌疫苗中，并开发修饰疫苗的一致化学合成，以提供用于生物学评价的材料。我们相信这项工作对公众健康非常重要，因为每年癌症夺去50多万美国人的生命。开发有效的抗癌疫苗将为利用人体免疫系统的力量对抗和预防癌症提供一种新的有价值的工具。

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.