NKG2D superagonist co-stimulation to enhance adaptive immunotherapy of cancer

NKG2D 超级激动剂共刺激增强癌症适应性免疫治疗

基本信息

批准号：
9158250
负责人：
JENNIFER D WU
金额：
$ 34.2万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2017-08-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9158250
关键词：
Accounting Address Agonist Antibodies Antigens Autoimmune Process B-Lymphocytes CD28 Antigens CD28 gene CD3 Antigens CD4 Positive T Lymphocytes CD8B1 gene Cells Chronic Clinic Complex Contracts Cytotoxic T-Lymphocytes Effectiveness Engineering Family Future Generations Goals Human Immune response Immunity Immunotherapy In Situ In Vitro Ligands Maintenance Malignant Neoplasms Mediating Memory Natural Killer Cells Outcome Signal Transduction Surface T cell response T cell therapy T-Cell Activation T-Cell Development T-Lymphocyte TNF gene Testing Therapeutic Therapeutic Effect Translating Tumor Antigens Tumor-Derived abstracting base cancer immunotherapy crosslink cytotoxicity empowered expectation functional status improved killings neoplastic cell neutralizing antibody novel novel strategies receptor response tumor tumor microenvironment

项目摘要

Abstract Effective T cell co-stimulation is critical for the primary induction and subsequent specific T cell responses. In addition to increased co-inhibitory signals, insufficient co-stimulatory tumor maintenance of antigen- microenvironment accounts for a great deal of the suboptimal activation and maintenance of tumor-killing CD8 T cells. Thus, one of the major goals in the immunotherapy of cancer is to provide sustainable co-stimulatory signal to empower the generation and persistence of effective tumor-killing CD8 T cells and ultimately to achieve durable tumor control. Yet, beyond engineered CAR-T cells that contain co-stimulatory motif in the engineered TCR, means to empower sustained in situ CD8 T cell co-stimulation are still far from expectations, due to the unsustainable expression of the canonical and activation-induced family of co-stimulatory receptors on CD8 T cells in the tumor microenvironment. In this proposal, we propose to activate the constitutively expressed human CD8 T cell co-stimulatory receptor NKG2D with a novel superagonist to amplify and sustain tumor antigen-specific CD8 T cell antitumor immunity. We hypothesize that therapy with NKG2D superagonist can augment T cell-mediated immunotherapy of cancer through providing sustainable magnitude of co- stimulation to induce effective and persistent antigen-specific immune responses in tumors. We propose three Specific Aims: 1) To delineate mechanisms whereby the NKG2D superagonist provides sustainable magnitude of co-stimulation to TCR/CD3 signaling; 2) To determine the impact of the NKG2D superagonist co- stimulation on cancer therapeutic effect of adoptive T cell therapy; 3) To determine the synergistic or collaborative cancer therapeutic effect of the NKG2D superagonist co-stimulation in combination with T cell checkpoint blockades. Providing that the NKG2D superagonist is being optimized for human use, if our hypothesis is proven, the therapy can be translated into clinics in the near future to significantly improve current practice of cancer immunotherapy.

抽象的有效的 T 细胞共刺激对于初次诱导和后续过程至关重要特异性 T 细胞反应。除了共抑制信号增加外，共刺激肿瘤也不足维持抗原- 微环境在很大程度上导致了肿瘤杀伤 CD8 的次优激活和维持 T 细胞。因此，癌症免疫治疗的主要目标之一是提供可持续的共刺激信号增强有效杀伤肿瘤 CD8 T 细胞的生成和持久性，并最终实现持久的肿瘤控制。然而，除了含有共刺激基序的工程化 CAR-T 细胞之外，工程TCR，增强持续原位CD8 T细胞共刺激的手段仍远未达到预期，由于共刺激受体的经典和激活诱导家族的不可持续表达肿瘤微环境中的 CD8 T 细胞。在本提案中，我们建议激活本构表达人 CD8 T 细胞共刺激受体 NKG2D 与新型超级激动剂来放大和维持肿瘤抗原特异性CD8 T细胞抗肿瘤免疫。我们假设 NKG2D 超级激动剂治疗可以通过提供可持续的协同作用来增强 T 细胞介导的癌症免疫治疗刺激在肿瘤中诱导有效且持久的抗原特异性免疫反应。我们提出三个具体目标：1) 描述 NKG2D 超级激动剂提供可持续作用的机制 TCR/CD3 信号传导的共刺激强度； 2) 确定 NKG2D 超级激动剂联合作用的影响刺激过继性 T 细胞疗法的癌症治疗效果； 3) 确定协同或 NKG2D超激动剂联合T细胞共刺激的协同癌症治疗效果检查站封锁。假设 NKG2D 超级激动剂正在针对人类使用进行优化，如果我们假设得到证实，该疗法可以在不久的将来转化为临床，以显着改善癌症免疫治疗的当前实践。