DNA-based Immune Phenotyping in HNSCC for Biomarkers of Response to Immunotherapy

HNSCC 基于 DNA 的免疫表型分析，作为免疫治疗反应的生物标志物

• 批准号: 10560607
• 负责人: Brock Clarke Christensen
• 金额: $ 64.97万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560607
• 关键词: Address; Adverse event; Biological Markers; Blood; Bone Marrow; Cancer Patient; Cell Separation; Cells; Clinical; Clone Cells; Comprehensive Cancer Center; Cryopreservation; DNA; DNA Methylation; Data; Development; Disease; Disease remission; Drug Costs; Epigenetic Process; Evaluation; Fingerprint; Funding; Generations; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Hematopoiesis; Human; Immune; Immune response; Immune system; Immunologic Markers; Immunologic Techniques; Immunologics; Immunophenotyping; Immunotherapeutic agent; Immunotherapy; Individual; Inflammation; Knowledge; Leukocytes; Libraries; Lymphocyte; Malignant Neoplasms; Measures; Mediating; Methodology; Methylation; Mutation; Myeloid-derived suppressor cells; Myelopoiesis; Nature; Nivolumab; Patient-Focused Outcomes; Patients; Pattern; Peripheral; Phenotype; Population; Prediction of Response to Therapy; Predictive Value of Tests; Production; Prognosis; Prognostic Marker; Property; Prospective Studies; Recurrence; Recurrent disease; Reproducibility; Retrospective Studies; Risk; Role; Site; Standardization; Stratification; Therapeutic Agents; Time; Tumor Immunity; Unresectable; Work; biomarker identification; blood treatment; cancer type; cell type; checkpoint therapy; chemotherapy; clinical application; clinical decision-making; cohort; cost effective; epigenome-wide association studies; granulocyte; immune checkpoint blockade; immune modulating agents; immunological status; immunomodulatory therapies; improved; in vivo; innovation; methylomics; monocyte; neutrophil; novel; novel marker; novel therapeutics; patient response; pembrolizumab; peripheral blood; phenotypic biomarker; predictive marker; prognostic; prognostic value; programmed cell death ligand 1; prospective; response; response biomarker; survivorship; tool; treatment duration; treatment response; tumor; tumor microenvironment

PROJECT SUMMARY/ABSTRACT Head and Neck Squamous Cell Carcinomas (HNSCCs) are devastating upper airway tumors that are associated with an immunosuppressive network impacting the tumor microenvironment, bone marrow and the peripheral blood compartments. The development of novel biomarkers of cancer immunity have not kept pace with breakthroughs in our understanding of cancer-associated inflammation and its relationship with abnormal hematopoiesis and the production of immunosuppressive leukocyte populations. Nor have biomarkers kept pace with clinical indications for use of immunomodulatory therapies. Here, we address the gap in clinically applicable immune biomarkers by first developing unique immuno-methylomic tools to identify aberrant peripheral immune cell populations, followed by the application of such tools for studying HNSCC survivorship. The FDA recently approved pembrolizumab with or without chemotherapy as a first-line treatment for metastatic, or unresectable recurrent disease, which is poised to dramatically increase the number of patients receiving immunotherapy for HNSCC, further underscoring the critical need to identify biomarkers of response to treatment, even before de facto issues of drug cost. Further, recent successful trials of immunomodulatory agents treating late stage HNSCC reveal that there is a crucial role for the immune system in disease survival and prognosis. To understand and quantify immune status, we propose to apply novel DNA methylation-based immune phenotyping biomarkers that will define the immune suppressive state and allow us to intensively study its relationship to immunotherapy treatment response in HNSCC. The proposed study will draw from two independent, comparable, prospectively collected patient cohorts at NCI-designated Comprehensive Cancer Centers. Results from single cell tracing approaches to follow clones of cells in-vivo in cancer patients showed dramatic evidence that the intrinsic ability to attract new immune cells to the tumor results in improved checkpoint blockade activity. This finding strongly supports our approach to identifying biomarkers of checkpoint blockade response through measures in the peripheral blood. As new immunotherapies are developed for HNSCC, it is crucial to mediate the effects of the host’s compromised immune system. The new generation of epigenetic techniques for immune profiling will provide biomarkers that are useful both in assessing immune status and in addressing mechanisms of immune modifiers.

项目摘要/摘要 头部和颈部方形细胞癌（HNSCCS）是毁灭性的上呼吸道肿瘤 通过影响肿瘤微环境的免疫抑制网络，骨髓和周围 血室。新型癌症免疫生物标志物的发展并没有使空间保持空间 我们对癌症相关感染的理解及其与异常的关系的突破 造血和免疫抑制白细胞种群的产生。生物标志物也没有跟上 使用免疫调节疗法的临床指示。在这里，我们解决了临床适用的差距 免疫生物标志物通过首先开发独特的免疫甲基组学工具来识别异常外周免疫 细胞种群，然后应用此类工具来研究HNSCC生存。 FDA最近 有或没有化学疗法的批准的pembrolizumab作为转移或无法切除的一线治疗 复发性疾病，被中毒以显着增加接受免疫疗法的患者数量 HNSCC，进一步强调了识别治疗反应的生物标志物的迫切需求，甚至在DE之前 事实上的药物成本问题。此外，最近对治疗后期的免疫调节剂的成功试验 HNSCC表明，免疫系统在疾病生存和预后中起着至关重要的作用。到 了解和量化免疫状态，我们建议采用新型DNA甲基化免疫物 表型生物标志物将定义免疫抑制状态，并使我们能够深入研究其 HNSCC中与免疫疗法治疗反应的关系。拟议的研究将从两个 在NCI指定的综合癌症下独立，可比较，前瞻性收集的患者队列 中心。单细胞追踪方法的结果跟随癌症患者的体内细胞克隆 戏剧性的证据表明，吸引新免疫细胞到肿瘤的内在能力可改善检查点 封锁活动。这一发现强烈支持我们识别检查点封锁的生物标志物的方法 通过外周血的措施来反应。由于HNSCC开发了新的免疫疗法，这是 对于介导宿主受损免疫系统的影响至关重要。新一代表观遗传学 免疫分析的技术将提供生物标志物，这些标志物在评估免疫状态和 解决免疫修饰剂的机制。