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消除患者体内的肿瘤细胞，并开​​发针对肿瘤变体生长的长期保护。随着对免疫系统的了解不断提高，人们对利用免疫调节疗法治疗癌症的热情也越来越高。该提案的目的是开发一种新机制来针对卵巢癌提供选择性免疫激活。我们建议用嵌合 NK 细胞受体转导 T 细胞，该受体可以像 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 的信号部分融合来产生嵌合 NKG2D 受体 (chNKG2D)。我们假设基于 chNKG2D 的免疫疗法将直接攻击卵巢癌细胞，产生细胞因子来激活宿主免疫，并导致长期无肿瘤生存。该提案的具体目标将解决以下问题： 1. 小鼠chNKG2D T细胞在体内消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细胞激活体内消除卵巢肿瘤细胞的关键宿主免疫机制是什么？ 3. chNKG2D T 细胞在多大程度上激活宿主 T 细胞并导致针对肿瘤再攻击的保护？ chNKG2D 受体方法提供了一种利用嵌合 NK 细胞受体来调用肿瘤特异性宿主反应的新方法，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 的信号传导域结合起来，创建了一种受体，允许 CTL 杀死肿瘤细胞并分泌促炎细胞因子。由于 NKG2D 配体在许多不同组织衍生的肿瘤上表达，这种方法有可能用于对抗多种癌症。总体目标是确定嵌合 NKG2D 受体消除卵巢癌并激活宿主免疫从而实现无肿瘤生存的有效性和机制。 公共健康相关性：该提案旨在了解一种称为嵌合 NKG2D 受体的新型免疫疗法的基本功能和有效性，该疗法利用肿瘤识别具有杀伤 T 细胞功能的自然杀伤细胞。我们相信这种基于细胞的疗法将提供一种强大的方法，使人的免疫细胞能够识别和攻击自身的肿瘤，从而消除肿瘤并实现卵巢癌的长期生存。

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.