HTS for the discovery of activators of NK cell cytotoxicity

HTS 用于发现 NK 细胞毒性激活剂

• 批准号: 10631030
• 负责人: David Wald
• 金额: $ 37.28万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631030
• 关键词: Activated Natural Killer Cell; Acute Myelocytic Leukemia; Address; Adverse event; Antigens; Biological; Biological Assay; Cancer Etiology; Cancer Patient; Cancer cell line; Cell Surface Receptors; Cellular immunotherapy; Cessation of life; Chemicals; Clinical; Clinical Trials; Collection; Cytolysis; Development; Dose; Enhancers; Epithelial ovarian cancer; Future; Hematologic Neoplasms; Immunodeficient Mouse; Immunotherapy; In Vitro; Lead; Libraries; Ligands; Lymphocyte; Lymphocyte Subset; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Mediator; Molecular; NK Cell Activation; NK cell therapy; Natural Killer Cells; Normal Cell; Patients; Phenotype; Predisposition; Property; Public Health; Refractory; Refractory Disease; Relapse; Series; Solid Neoplasm; System; Testing; Therapeutic; Woman; Work; cancer cell; cancer therapy; cell killing; circulating leukemia cell; clinical efficacy; cytotoxic; cytotoxicity; human cancer mouse model; human model; improved; in vivo; insight; metastatic colorectal; neoplastic cell; novel; receptor; safety testing; small molecule; success

Abstract Natural killer (NK) cells are lymphocytes that are capable of killing malignant cells without antigen-specific receptor recognition. Due to this property, NK cells have been utilized for adoptive immune cell therapy for a variety of malignancies. Despite limited success for hematologic malignancies, the therapeutic potential of NK cell therapy for cancer has been limited by the insufficient cytotoxic activity of NK cells particularly for solid tumors. Due to the ability of NK cells to specifically target cancer cells and avoid killing of normal cells, we hypothesize that enhancing the cytotoxic activity of NK cells can lead to enhanced efficacy of NK cell therapies for cancer. As the molecular mediators regulating NK cell cytotoxic activity are still not fully characterized, we will conduct a small molecule high throughput compound library screen to identify novel mediators of NK cell cytotoxic activity. The purpose of this work is to identify small molecules that can be further developed for therapeutic purposes as well as to reveal important probes to elucidate mechanistic insights into NK cell activity that may enable future targeted approaches. In the first aim, we will identify compounds that enhance NK cell killing of ovarian cancer cells through a HTS of a diverse 300k small molecule collection. In the second aim, the primary hits will be tested in a series of secondary assays to identify the most promising hits. The most promising hits will then undergo biological characterization in vitro and in vivo. It is hoped that this work will lead to the identification of promising approaches to improve NK cell therapy for cancer patients.

摘要 自然杀伤(NK)细胞是一种在没有抗原特异性的情况下能够杀死恶性细胞的淋巴细胞 受体识别。由于这一特性，NK细胞已被用于过继免疫细胞治疗 各种恶性肿瘤。尽管治疗血液系统恶性肿瘤的成功有限，但NK细胞的治疗潜力 肿瘤的细胞治疗一直受到NK细胞细胞毒活性不足的限制，特别是对固体细胞 肿瘤。由于NK细胞能够特异性地靶向癌细胞并避免杀死正常细胞，我们 假设增强NK细胞的细胞毒活性可以增强NK细胞治疗的疗效 治疗癌症。由于调节NK细胞细胞毒活性的分子介体仍未完全确定，我们 将进行小分子高通量化合物文库筛选，以确定NK细胞的新介体 细胞毒活性。这项工作的目的是识别可以进一步开发用于 治疗目的以及揭示重要的探针以阐明对NK细胞的机制洞察 可能实现未来有针对性的方法的活动。在第一个目标中，我们将识别出 通过多种300K小分子集合的HTS增强NK细胞对卵巢癌细胞的杀伤作用。 在第二个目标中，一次命中将在一系列二次化验中进行测试，以确定最 很有希望的热门歌曲。然后，最有希望的重磅炸弹将在体外和体内进行生物学表征。它 希望这项工作将导致确定有希望的方法来改进NK细胞治疗 为癌症患者准备的。