Novel Strategies for Immunotherapy fo Cancer

癌症免疫治疗新策略

• 批准号: 6913680
• 负责人: Rongfu Wang
• 金额: $ 27.77万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6913680
• 关键词: Burkitt' s lymphoma; Epstein Barr virus; Hodgkin' s disease; MHC class II antigen; cellular immunity; clinical research; cytokine; dendritic cells; disease /disorder model; genetically modified animals; helper T lymphocyte; human tissue; immune response; laboratory mouse; leukocyte activation /transformation; nasopharyngeal neoplasms; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; peptides; therapy design /development; tumor antigens; virus antigen; virus related neoplasm /cancer

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.

描述（由申请人提供）：针对EBV抗原的T细胞反应已在伯基特淋巴瘤（BL）、鼻咽癌（NPC）和霍奇金病（HD）中引起，但不足以根除肿瘤细胞。目前的方法主要集中在CD8+T效应细胞上，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，CD4+ T（辅助）细胞在启动和维持宿主对癌症的免疫反应中起着核心作用。虽然已经报道了一些MHC ii类限制性EBNA1肽，但这些肽及其同源CD4+ T细胞在抗肿瘤免疫中的作用尚不清楚。因此，建立临床前肿瘤模型对于开发增强抗肿瘤免疫反应的新策略至关重要。我们假设，来自EBNA1的MHC ii类限制性肽以及来自以前未被识别的肿瘤抗原，可以在ebv阳性肿瘤细胞中被识别出来，并用于激活CD4+ T细胞，从而产生更有效的抗肿瘤免疫。为了验证这一假设，我们建议鉴定和评估来自evb相关肿瘤的MHC ii类限制性病毒/肿瘤肽。有了这些辅助性T表位，它们的最佳使用将需要对有效的疫苗策略和抗原特异性CD4+ T细胞的抗肿瘤作用有更多的了解。缺乏eb病毒相关肿瘤的动物模型是获得此类知识和了解开发针对eb病毒相关癌症的有效疫苗的主要障碍。因此，我们进一步提出建立以EBNA1表达为特征的小鼠BL模型，并利用该模型通过Pl实验室开发的新型抗原递送系统来确定CD4+ 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CD4+ T细胞介导的抗肿瘤免疫机制，以确定CD4+ T细胞是否通过直接或间接杀伤肿瘤机制，以及/或通过CD4+ 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，并为开发有效的癌症疫苗的新方法奠定基础。