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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.

摘要