Project 1

项目1

基本信息

批准号：
10434087
负责人：
Jiyoung Ahn
金额：
$ 28.09万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-19 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10434087
关键词：
Adaptive Immune System Adjuvant Adjuvant Study Affect Animals Attenuated Biological Assay Biological Markers Blinded Blood Blood specimen CTLA4 blockade CTLA4 gene Cells Clinical Clinical Trials Combination immunotherapy Controlled Clinical Trials Data Exposure to Feces Genes Goals Human Immune Immune response Immunity Immunologic Markers Immunotherapy Inflammatory Integration Host Factors Intervention Lead Mediating Metastatic Melanoma Microbe Nature Outcome PD-1 blockade Pathway interactions Patient Care Patients Peripheral Phase Phenotype Play Publications Randomized Randomized Controlled Clinical Trials Regulatory T-Lymphocyte Relapse Reporting Research Resected Role Sampling Series Serum Serum Proteins Standardization T cell response T-Lymphocyte Testing Toxic effect Treatment-related toxicity adaptive immune response anti-CTLA4 anti-PD-1 anti-cancer base biomarker identification biomarker performance cancer immunotherapy checkpoint inhibition clinical efficacy clinical outcome assessment clinical predictors cohort gut bacteria gut microbiome gut microbiota high risk immune checkpoint blockade improved inhibitor innovation melanoma microbial microbial host microbiome novel peripheral blood personalized immunotherapy predict clinical outcome predictive marker predictive signature programmed cell death protein 1 prospective relapse prediction response side effect stool sample

项目摘要

PROJECT 1 SUMMARY We hypothesize that interplay between host immune responses and the gut microbiota affect the efficacy and toxicity of immune checkpoint inhibition (ICI) in melanoma patients. Increasing evidence suggests that gut microbiota play important roles in regulating the innate and adaptive immune response to cancer immunotherapy. We and others have provided compelling evidence that the gut microbiome is associated with the efficacy and the toxicity of immunotherapy. We also showed that novel baseline pre-treatment T-cell phenotypes and the levels and suppressive function of T regulatory cells in the peripheral blood were associated with increased relapse-free survival (RFS) after PD-1 blockade in melanoma. Moreover, we found that alterations in serum protein immune pathways were associated with decreased survival with PD-1 blockade, underlining the importance of host immune responses for immunotherapy outcomes. Nonetheless, no definitive, large scale human studies have identified the gut microbial taxa associated with the efficacy and/or toxicity of immunotherapy, nor investigated their relationships with host immune responses. The goal of Project 1 is to identify microbial and host immune biomarkers that predict the efficacy and toxicity of ICI in a randomized phase III adjuvant trial testing combination PD-1/CTLA-4 blockade versus PD-1 alone in patients with high-risk resected stage IIIB/C and IV melanoma. As part of a large, well-controlled randomized and blinded trial (n=2000; a subset of n=1500 available blood/stool samples), we will evaluate gut microbiota in stool and a series of innovative biomarkers in serum and peripheral blood immune cells, and examine the utility of these biomarkers to predict clinical efficacy and toxicity from immunotherapy (Aims 1 and 2). Based on integration of these biomarkers, we will additionally define cohorts of patients who may derive differential benefit from combination versus single-agent checkpoint blockade (Aim 3). This study, based on a large clinical trial with standardized treatments and clinical outcome as well as toxicity assessments, will provide excellent power for biomarker identification with rigorous replications. This research will improve patient care by defining predictive biomarkers and developing a predictive classifier – using easily obtainable stool, serum, and blood samples – that can facilitate personalized immunotherapy decisions. Finally, given the modifiable nature of gut bacteria, findings could lead to tailored microbe-targeted interventional approaches to improve the efficacy of, and attenuate the toxicity of, ICI.

项目1摘要我们假设宿主免疫反应与肠道菌群之间的相互作用会影响效率和黑色素瘤患者免疫抑制（ICI）的毒性。越来越多的证据表明肠道微生物群在调节对癌症的先天和适应性免疫方面起着重要作用免疫疗法。我们和其他人提供了令人信服的证据，表明肠道微生物组与免疫疗法的效率和毒性。我们还显示了新型基线预处理T细胞表型以及周围血液中T调节细胞的水平和抑制作用与在黑色素瘤中PD-1阻断后，无继电器生存率（RFS）增加。而且，我们发现改变在血清蛋白质中，免疫途径与PD-1阻滞的生存率降低有关，强调宿主免疫疗法反应对免疫疗法结果的重要性。尽管如此，没有确定的大规模人类研究已经确定了与效率和/或毒性相关的肠道微生物分类群免疫疗法，也没有研究他们与宿主免疫反应的关系。项目1的目的是确定微生物和宿主免疫生物标志物，以预测效率和毒性 ICI在随机阶段III中调整试验测试组合PD-1/CTLA-4 blocade与PD-1仅在具有高风险的IIIB/C和IV黑色素瘤的患者。作为大型，控制良好的随机分析的一部分和盲试验（n = 2000； n = 1500个可用血/粪便样本的子集），我们将评估肠道微生物群粪便和一系列在血清和外周血免疫细胞中的创新生物标志物，并检查效用这些生物标志物可以预测免疫疗法的临床效率和毒性（目标1和2）。基于这些生物标志物的整合，我们还将定义可能获得差异益处的患者同类从组合与单格检查点封锁（AIM 3）。这项研究，基于一项大型临床试验标准化治疗和临床结果以及毒性评估将为生物标志物识别严格的复制。这项研究将通过定义预测生物标志物并开发预测分类器来改善患者护理 - 使用易于获得的凳子，血清和血液样本 - 可以促进个性化免疫疗法决定。最后，鉴于肠道细菌的可修改性质，发现可能导致量身定制的微生物。提高ICI的效率并衰减毒性的介入方法。