Novel Strategies for Immunotherapy of Cancer

描述(申请人提供)：在Burkitt淋巴瘤(BL)、鼻咽癌(NPC)和霍奇金病(HD)中已经激发了针对EBV抗原的T细胞反应，但还不足以根除肿瘤细胞。目前的方法主要集中在CD8+T效应细胞似乎不足以产生最佳的抗肿瘤免疫。越来越多的人类和动物研究表明，CD4+T(辅助)细胞在启动和维持宿主对癌症的免疫反应中发挥着核心作用。虽然已经报道了一些MHC II类限制性EBNA1多肽，但这些多肽及其同源的CD4+T细胞在抗肿瘤免疫中的作用尚不清楚。因此，开发一种临床前肿瘤模型对于开发增强抗肿瘤免疫反应的新策略是至关重要的。我们推测，来自EBNA1和以前未知的肿瘤抗原的MHC II类限制性多肽可以在EBV阳性的肿瘤细胞中被识别出来，并被用来激活CD4+T细胞，导致更强大的抗肿瘤免疫。为了验证这一假设，我们建议从EVB相关肿瘤中识别和评估MHC II类限制性病毒/肿瘤多肽。有了这些T辅助表位，它们的最佳使用将需要更多关于有效疫苗策略和抗原特异性CD4+T细胞的抗肿瘤作用的知识。缺乏EBV相关肿瘤的动物模型是获得此类知识和了解开发有效的EVB相关癌症疫苗的主要障碍。因此，我们进一步建议建立一种以EBNA1表达为特征的小鼠白血病模型，并利用该模型通过本实验室开发的一种新的抗原递送系统来确定CD4+T细胞在抗白血病细胞免疫反应中的作用。最后，我们计划阐明CD_4~+T细胞介导的抗肿瘤免疫的机制，以确定CD_4~+T细胞是否通过直接或间接的肿瘤杀伤机制和/或通过CD_4~+T细胞分泌的细胞因子发挥抗肿瘤作用。预计这些研究将推动癌症免疫治疗领域的发展，并为开发有效的癌症疫苗的新方法提供基础。

DESCRIPTION (provided by applicant): T cells responses against the EBV antigens have been elicited in Burkitt lymphoma (BL), nasopharyngeal cancer (NPC) and Hodgkin disease (HD), but have been insufficient to eradicate tumor cells. Current approach mainly focuses on CD8+T effector cells appears inadequate for the generation of optimal antitumor immunity. Increasing evidence from both human and animal studies indicates that CD4+ T (helper) cells play a central role in initiating and maintaining the host immune responses against cancer. While a few MHC class II-restricted EBNA1 peptides have been reported, the role of such peptides and their cognate CD4+ T cells in antitumor immunity is unknown. Thus, it is critical to develop a preclinical tumor model for developing novel strategies to enhance antitumor immune responses. We hypothesize that MHC class II-restricted peptides from EBNA1 as well as from previously unrecognized tumor antigens, can be identified in EBV-positive tumor cells and used to activate CD4+ T cells, leading to more potent antitumor immunity. To test this hypothesis, we propose to identify and evaluate MHC class II-restricted viral/tumor peptides from EVB-associated tumors. With these T helper epitopes in hand, their optimal use will require greater knowledge of effective vaccine strategies and the antitumor role of antigen-specific CD4+ T cells. A lack of an animal model for EBV-associated tumors poses a major obstacle for obtaining such knowledge and understanding of development of effective vaccines against EVB-associated cancer. Thus, we further propose to establish a murine BL model characterized by expression of EBNA1, and exploit it to define the role of CD4+ T cells in cellular immune responses against BL tumors by a novel antigen delivery system developed in the Pl's laboratory. Finally, we plan to elucidate the mechanism of CD4+ T-cell-mediated antitumor immunity, to determine whether CD4+ T cells exert antitumor effects by direct or indirect tumor killing mechanisms, and/or through the role of cytokines secreted by CD4+ T cells. It is anticipated that these studies will advance the field of immunotherapy of cancer and provide a foundation for the development of novel approaches for effective cancer vaccines.