Chimeric NKG2D receptors in ovarian cancer immunotherapy

描述(由申请人提供)：免疫疗法有可能选择性地消除患者体内的肿瘤细胞，并发展出针对肿瘤变异的长期保护。随着对免疫系统知识的提高，人们越来越热衷于用免疫调节疗法治疗癌症。这项建议的目的是开发一种新的机制，以提供针对卵巢癌的选择性免疫激活。我们建议用嵌合的NK细胞受体转导T细胞，它可以像NK细胞一样识别肿瘤细胞，并直接激活T细胞。这些嵌合受体是通过将NKG2D基因与CD3zeta的信号部分融合而产生的嵌合NKG2D受体(ChNKG2D)。我们推测，基于chNKG2D的免疫治疗将提供对卵巢癌细胞的直接攻击，产生细胞因子来激活宿主免疫，并导致长期无瘤生存。这项建议的具体目的将解决以下问题：1.小鼠chNKG2D T细胞在体内清除卵巢肿瘤细胞的程度如何，这些T细胞是否存在潜在的自身免疫反应？2.chNKG2D T细胞在体内激活哪些关键的宿主免疫机制来清除卵巢肿瘤细胞？3.chNKG2D T细胞在多大程度上激活宿主T细胞并导致对肿瘤再攻击的保护？ChNKG2D受体方法提供了一种新的方法，利用嵌合的NK细胞受体来激活肿瘤特异性宿主反应，以指导针对肿瘤细胞的免疫反应。我们将NKG2D受体的配体特异性与CD36的信号域结合起来，创造了一种受体，允许CTL杀伤肿瘤细胞并分泌促炎细胞因子。由于NKG2D的配体在来自许多不同组织的肿瘤上的表达，这种方法具有对抗多种癌症的潜力。总体目标是确定嵌合NKG2D受体消除卵巢癌和激活宿主免疫从而实现无瘤生存的有效性和机制。与公共卫生相关：这项提案旨在了解一种名为嵌合NKG2D受体的新型免疫疗法的潜在功能和有效性，该疗法使用具有杀伤T细胞功能的自然杀伤细胞的肿瘤识别。我们相信，这种基于细胞的疗法将提供一种强大的手段，使人的免疫细胞能够识别和攻击自己的肿瘤，并导致卵巢癌的肿瘤消除和长期生存。

DESCRIPTION (provided by applicant): Immunotherapy has the potential to allow selective elimination of tumor cells in patients and the development of long-term protection against outgrowth of tumor variants. As knowledge of the immune system improves, there has been an increased enthusiasm for treating cancer with immune modulating therapies. The aim of this proposal is the development of a new mechanism to deliver selective immune activation against ovarian carcinomas. We propose to transduce T cells with chimeric NK cell receptors that can recognize tumor cells as NK cells do and directly activate T cells. These chimeric receptors are produced by fusing the NKG2D gene with the signaling portion of CD3zeta to create a chimeric NKG2D receptor (chNKG2D). We hypothesize that chNKG2D based immunotherapy will provide both direct attack on ovarian carcinoma cells, produce cytokines to activate host immunity, and lead to long-term tumor free survival. The specific aims of this proposal will address the following questions: 1. To what extent do murine chNKG2D T cells eliminate ovarian tumor cells in vivo and are there potential autoimmune responses of these T cells? 2. What are the key host immune mechanisms that chNKG2D T cells activate to eliminate ovarian tumor cells in vivo? 3. To what extent do chNKG2D T cells activate host T cells and lead to protection against tumor rechallenge? The chNKG2D receptor approach provides a novel means to invoke tumor-specific host responses using chimeric NK cell receptors to direct the immune response against tumor cells. We have combined the ligand specificity of the NKG2D receptor with the signaling domain of CD36 to create a receptor that allows CTLs to kill tumor cells and secrete proinflammatory cytokines. Due to the expression of ligands for NKG2D on tumors derived from many different tissues, this approach has the potential to be useful against a wide variety of cancers. The overall goal is to determine the effectiveness and mechanisms by which chimeric NKG2D receptors eliminate ovarian carcinomas and activate host immunity resulting in tumor-free survival. PUBLIC HEALTH RELEVANCE: This proposal aims to understand the underlying function and effectiveness of a novel immunotherapy, called chimeric NKG2D receptors, that uses the tumor recognition of a natural killer cell with the function of killer T cells. We believe this cell-based therapy will provide a robust means to allow a person's immune cells to recognize and attack their own tumor and result in tumor elimination and long-term survival in ovarian cancer.