(PQ8) Predictive biomarkers for the onset of immune-related adverse events associated with PD-1 blockade

(PQ8) 与 PD-1 阻断相关的免疫相关不良事件发生的预测生物标志物

• 批准号: 9806456
• 负责人: Adam Mor
• 金额: $ 26.24万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9806456
• 关键词: Academic Medical Centers; Address; Affect; Aftercare; Antigens; Autoimmune Process; Autoimmunity; Automobile Driving; Biological Markers; Biological Models; Blocking Antibodies; CD8-Positive T-Lymphocytes; Cancer Patient; Cell physiology; Cells; Clinical; Clinical Trials; Clonality; Clone Cells; Data; Development; Diabetes Mellitus; Event; Exhibits; Experimental Models; Future; Gene Expression; Gene Expression Profile; Genetic Polymorphism; Genetic Transcription; Goals; Grant; Human; Human Resources; Immune Tolerance; Immune checkpoint inhibitor; Immune system; Immunologic Markers; Immunologic Receptors; Immunosuppressive Agents; Immunotherapy; Inflammation; Inflammatory; Inflammatory Response; Institutional Review Boards; Lead; Life; Light; Malignant Neoplasms; Malignant neoplasm of lung; Mediator of activation protein; Molecular; Operations Research; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Peripheral; Play; RNA; Reaction; Reporting; Research; Research Personnel; Role; SLEB2 gene; Sampling; Self Tolerance; Severities; Signal Pathway; Signal Transduction; T cell response; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Thoracic Oncology; Time; Tissue-Specific Gene Expression; Tissues; Tumor Escape; anti-PD1 therapy; anti-tumor immune response; autoreactive T cell; autoreactivity; base; cancer immunotherapy; checkpoint inhibition; clinical biomarkers; collaborative environment; cytotoxicity; design; experience; experimental study; follow-up; genetic approach; genetic signature; guided inquiry; immune clearance; immune-related adverse events; insight; neoplastic cell; next generation; novel marker; novel strategies; outcome forecast; peripheral tolerance; potential biomarker; predictive marker; receptor; sample collection; single-cell RNA sequencing; supportive environment; transcriptomics; tumor; tumor microenvironment

PROJECT ABSTRACT The proposed study, Predictive biomarkers for the onset of immune-related adverse events associated with PD-1 blockade, addresses NCI’s Provocative Question 8 (PQ8): What are the predictive biomarkers for the onset of immune-related adverse events associated with checkpoint inhibition, and are they related to markers for efficacy? Programmed cell death-1 (PD-1) is an essential inhibitory receptor in T cells. Antibodies that block PD-1 augment anti-tumor immune responses and represent a powerful therapeutic paradigm. There are currently over 400 clinical trials targeting PD-1, highlighting its emerging potential in cancer immunotherapy. Unfortunately, 1 in 4 patients who receive anti-PD-1 treatment develop immune-related adverse events (irAEs), including autoimmunity. As such, elucidating the mechanisms of immune-tolerance breakdown, which lead to excessive inflammation in cancer patients treated with immune-checkpoint inhibitors (such as anti-PD-1), presents a formidable opportunity to understand the molecular underpinnings of irAEs and to identify predictive biomarkers of irAEs in order to develop safer next-generation immunotherapies. To achieve this goal it is essential to understand how PD-1 blockade reshapes homeostatic T cell responses. We propose to uncover the repertoire diversity and the specific gene expression signatures of antigen-experienced T cells from patients undergoing anti-PD-1 therapy, via two Specific Aims: 1) to define T cell-specific gene expression signatures that distinguish patients who develop irAEs following anti-PD-1 therapy; and 2) to test the hypothesis that anti-PD-1 therapy decreases T cell repertoire diversity in patients who develop irAEs. We anticipate that our findings will shed light on the molecular complexity of both T cell repertoire transition and signaling dynamics during the development of irAEs. Supported by preliminary data, this project will apply new approaches to uncover the molecular mechanisms underlying irAEs. The proposed project will combine transcriptional and clonal repertoire analyses of T cells from lung cancer patients treated with anti-PD-1, to elucidate mechanisms of self-tolerance breakdown in immunotherapies. Within the proposed two years, we will examine PD-1 associated signaling clusters pathways in the setting of irAEs. These studies will reveal the immuno-pathogenesis of irAEs and will likely reveal both predictive and severity biomarkers for irAEs.

项目摘要 拟议的研究，即与免疫相关广告事件发作的预测生物标志物 使用PD-1桶，解决了NCI的挑衅性问题8（PQ8）：什么是预测性生物标志物 与检查点抑制相关的免疫相关不良事件的发作，它们是否与 放松标记？ 程序性细胞死亡1（PD-1）是T细胞中必不可少的抑制受体。阻断PD-1的抗体 增强抗肿瘤免疫调查并代表强大的热范式。目前有 针对PD-1的400多个临床试验，突出了其在癌症免疫疗法中的新兴潜力。 不幸的是，接受抗PD-1治疗的四分之一的患者中有1例发展了与免疫相关的广告事件（IRAES）， 包括自身免疫性。因此，阐明了免疫容忍分解的机制，导致 通过免疫切除点抑制剂（例如抗PD-1）治疗的癌症患者过度炎症， 提供了一个强大的机会，可以理解伊拉斯的分子基础并确定预测性 伊拉斯的生物标志物是为了开发更安全的下一代免疫疗法。为了实现这一目标是 重要的是要了解PD-1桶如何重塑体内稳态T细胞反应。我们建议发现 曲目多样性和来自抗原经验的T细胞的特定基因表达特征 接受抗PD-1治疗的患者通过两个特定目的：1）定义T细胞特异性基因表达 区分抗PD-1治疗后出现伊拉斯的患者的签名； 2）测试 假设抗PD-1治疗可降低发育伊拉斯患者的T细胞库多样性。我们 预计我们的发现将阐明T细胞库的分子复杂性和 IRAES开发过程中的信号动力学。在初步数据的支持下，该项目将应用新的 揭示伊拉斯基本机制的方法。拟议的项目将结合起来 对抗PD-1治疗的肺癌患者的T细胞的转录和克隆曲目分析， 阐明免疫疗法中自耐分解的机制。在提议的两年内，我们将 在IRAE的环境中检查PD-1相关的信号群集群集途径。这些研究将揭示 伊拉斯的免疫致病发生，可能会揭示伊拉斯的预测性和严重性生物标志物。