Chimeric NKG2D receptors in ovarian cancer immunotherapy

免疫疗法有可能选择性地消除患者体内的肿瘤细胞和 针对肿瘤变异体生长的长期保护的发展。作为免疫系统的知识 随着系统的改善，人们越来越热衷于用免疫调节来治疗癌症 治疗。这项提议的目的是开发一种新的机制来提供选择性免疫 激活对卵巢癌的治疗。我们建议用嵌合的NK细胞受体转导T细胞 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的信号部分融合产生嵌合NKG2D 受体(ChNKG2D)。 我们推测，基于chNKG2D的免疫治疗将提供对卵巢癌的直接攻击 细胞，产生细胞因子以激活宿主免疫，并导致长期无肿瘤生存。具体的 这项提案的目标将涉及以下问题： 1.小鼠chNKG2D T细胞体内清除卵巢肿瘤细胞的能力及潜力 这些T细胞的自身免疫反应？ 2.chNKG2D T细胞激活清除卵巢肿瘤的关键宿主免疫机制是什么 体内的细胞？ 3.chNKG2D T细胞在多大程度上激活宿主T细胞并导致对肿瘤的保护 重新挑战？ ChNKG2D受体方法提供了一种新的方法来激活肿瘤特异性宿主反应 嵌合的NK细胞受体引导针对肿瘤细胞的免疫反应。我们已经将配体结合在一起了 NKG2D受体与CD3信号域的特异性，以创建允许CTL的受体 杀死肿瘤细胞并分泌促炎细胞因子。由于NKG2D配体的表达 肿瘤起源于许多不同的组织，这种方法有可能对广泛的 各种癌症。总体目标是确定嵌合体的有效性和机制 NKG2D受体可清除卵巢癌并激活宿主免疫，从而实现无瘤生存。这项建议旨在了解一种新的免疫疗法的潜在功能和有效性， 称为嵌合NKG2D受体，它使用具有以下功能的自然杀伤细胞的肿瘤识别 杀伤T细胞。我们相信这种基于细胞的疗法将提供一种强大的手段，让一个人的免疫 细胞识别和攻击自己的肿瘤，并导致肿瘤消除和长期存活 卵巢癌。

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 signalling 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 CD3¿ 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. 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.