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Chimeric NKG2D receptors in ovarian cancer immunotherapy

卵巢癌免疫治疗中的嵌合 NKG2D 受体

基本信息

批准号：
8267726
负责人：
Charles L. Sentman
金额：
$ 32.18万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8267726
关键词：
Address Animals Autoimmune Process Autoimmune Responses Blood CD3 Antigens CD94 Antigen Cell Therapy Cells Clinical Defect Development Dose Effectiveness Genes Goals Host resistance Immune Immune response Immune system Immunity Immunotherapy Individual Inflammatory Kinetics Knowledge Lead Leukocytes Ligands Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of ovary Modeling Mus Natural Killer Cells Ovarian Carcinoma Patients Persons Regulatory T-Lymphocyte Role Signal Transduction Specificity T cell response T cell therapy T-Cell Receptor T-Lymphocyte Testing Tissues Tumor Burden Tumor Immunity Tumor-Derived Vaccination Variant base cancer immunotherapy cytokine immune activation improved in vivo killer T cell killings macrophage neoplastic cell novel novel strategies ovarian neoplasm receptor response trafficking tumor tumor growth

项目摘要

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.

免疫疗法有可能选择性消除患者体内的肿瘤细胞，并使其开发针对肿瘤变体生长的长期保护。作为免疫系统的知识随着免疫系统的改善，人们越来越热衷于用免疫调节治疗癌症。治疗该提案的目的是开发一种新的机制，激活抗卵巢癌。我们建议用嵌合NK细胞受体来刺激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的信号传导部分融合产生嵌合NKG2D 受体（chNKG2D）。我们假设基于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，并导致长期无肿瘤存活。具体本提案的目的将解决以下问题： 1.鼠chNKG2D T细胞在体内消除卵巢肿瘤细胞的程度如何？这些T细胞的自身免疫反应？ 2. chNKG2D T细胞激活消除卵巢肿瘤的关键宿主免疫机制是什么体内细胞？ 3. chNKG2D T细胞在多大程度上激活宿主T细胞并导致抗肿瘤保护再激发？ chNKG2D受体方法提供了一种新的方法，使用嵌合NK细胞受体以指导针对肿瘤细胞的免疫应答。我们结合了配体 NKG2D受体与CD3信号结构域的特异性，以产生允许CTL的受体杀死肿瘤细胞并分泌促炎细胞因子。由于NKG2D的配体在细胞上的表达，肿瘤来源于许多不同的组织，这种方法有可能是有用的，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受体消除卵巢癌并激活宿主免疫力，导致无肿瘤生存。该提案旨在了解新型免疫疗法的潜在功能和有效性，称为嵌合NKG2D受体，它利用自然杀伤细胞的肿瘤识别功能，杀手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，细胞识别和攻击自己的肿瘤，导致肿瘤消除和长期生存，卵巢癌