Chimeric NKG2D receptors in ovarian cancer immunotherapy

卵巢癌免疫治疗中的嵌合 NKG2D 受体

• 批准号: 8074911
• 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
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8074911
• 关键词: Address; Animals; Autoimmune Process; Autoimmune Responses; Blood; CD3 Antigens; CD36 gene; CD94 Antigen; Cell Therapy; Cells; Clinical; Defect; Development; Dose; Effectiveness; Genes; Goals; Health; 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 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

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.

描述（由申请人提供）：免疫疗法有可能在患者中选择性消除肿瘤细胞，并产生长期保护肿瘤变异的生长。随着免疫系统的知识的提高，通过免疫调节疗法治疗癌症的热情增加了。该提案的目的是开发一种新机制，以对卵巢癌进行选择性免疫激活。我们建议用嵌合NK细胞受体转导T细胞，这些嵌合NK细胞受体可以像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的信号传导部分融合以形成嵌合NKG2D受体（CHNKG2D）来产生的。我们假设基于CHNKG2D的免疫疗法将对卵巢癌细胞提供直接攻击，产生细胞因子以激活宿主免疫，并导致长期无肿瘤的生存率。该提案的具体目的将解决以下问题：1。鼠chnkg2d T细胞在多大程度上消除了体内卵巢肿瘤细胞，并且这些T细胞是否有潜在的自身免疫反应？ 2。CHNKG2D T细胞激活以消除体内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细胞并防止肿瘤补偿？ CHNKG2D受体方法提供了一种新型手段，可以使用嵌合NK细胞受体调用肿瘤特异性宿主反应，以指导针对肿瘤细胞的免疫反应。我们已经将NKG2D受体的配体特异性与CD36的信号传导结构域结合在一起，以创建一个受体，该受体允许CTL杀死肿瘤细胞并分泌促炎细胞因子。由于NKG2D的配体在源自许多不同组织的肿瘤上的表达，因此这种方法有可能对各种癌症有用。总体目标是确定嵌合NKG2D受体消除卵巢癌的有效性和机制，并激活宿主免疫，从而导致无肿瘤生存率。 公共卫生相关性：该提案旨在了解一种新型免疫疗法的潜在功能和有效性，称为嵌合NKG2D受体，该受体利用肿瘤对杀伤T细胞功能的自然杀伤细胞的识别。我们认为，这种基于细胞的疗法将提供一种可靠的手段，使人的免疫细胞能够识别和攻击自己的肿瘤，并导致消除肿瘤和长期生存。