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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘