Novel Strategies for Immunotherapy of Cancer

描述（由申请人提供）：在伯基特淋巴瘤（BL）、鼻咽癌（NPC）和霍奇金病（HD）中已引发针对EBV抗原的T细胞应答，但不足以根除肿瘤细胞。目前的方法主要集中在CD 8 +T效应细胞似乎不足以产生最佳的抗肿瘤免疫。来自人类和动物研究的越来越多的证据表明，CD 4 + T（辅助）细胞在启动和维持宿主对癌症的免疫应答中起着核心作用。虽然已经报道了一些MHC II类限制性EBNA 1肽，但这些肽及其同源CD 4 + T细胞在抗肿瘤免疫中的作用尚不清楚。因此，开发临床前肿瘤模型对于开发增强抗肿瘤免疫应答的新策略至关重要。我们假设来自EBNA 1以及以前未识别的肿瘤抗原的MHC II类限制性肽可以在EBV阳性肿瘤细胞中鉴定并用于激活CD 4 + T细胞，从而产生更有效的抗肿瘤免疫。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/肿瘤肽。有了这些辅助性T细胞表位，它们的最佳使用将需要更好地了解有效的疫苗策略和抗原特异性CD 4 + T细胞的抗肿瘤作用。缺乏EBV相关肿瘤的动物模型对获得这种知识和理解开发针对EVB相关癌症的有效疫苗构成了主要障碍。因此，我们进一步提出建立以EBNA 1表达为特征的小鼠BL模型，并利用其通过PI实验室开发的新型抗原递送系统来确定CD 4 + T细胞在针对BL肿瘤的细胞免疫应答中的作用。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的作用发挥抗肿瘤作用。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.