The roles of EBV-specific T cells in response to checkpoint blockade immunotherapy of EBV-driven nasopharyngeal carcinoma

EBV特异性T细胞在EBV驱动的鼻咽癌检查点阻断免疫治疗中的作用

• 批准号: 10681300
• 负责人: Evan Newell
• 金额: $ 60.34万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681300
• 关键词: Adoptive Immunotherapy; Aftercare; American Association of Cancer Research; Biopsy; Biopsy Specimen; Blood; Blood specimen; CD8-Positive T-Lymphocytes; Cancer Center; Cells; Characteristics; Clinical; Clinical Trials; Clone Cells; Cytometry; Data; Diagnosis; Enrollment; Epstein-Barr Virus-Related Malignant Neoplasm; Far East; Freezing; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genetic Transcription; Goals; HLA-DR Antigens; Head and Neck Cancer; Human Herpesvirus 4; Immune; Immune Evasion; Immune response; Immunohistochemistry; Immunologic Surveillance; Immunologics; Immunotherapeutic agent; Immunotherapy; Infiltration; Lymphocyte; Malignant Neoplasms; Mediating; Memory; Metastatic/Recurrent; Methods; Nasopharynx Carcinoma; Newly Diagnosed; Outcome; Participant; Patient Selection; Patients; Pattern; Peptide/MHC Complex; Peripheral; Peripheral Blood Mononuclear Cell; Persons; Phase II Clinical Trials; Phenotype; Population; Prevalence; Publishing; Role; Sampling; Singapore; Sorting; Southeastern Asia; Stains; Survival Rate; T cell receptor repertoire sequencing; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Testing; Time; Tissues; Tumor Tissue; Tumor-Infiltrating Lymphocytes; Validation; Virus Diseases; anti-CTLA4; anti-PD-1; anti-PD1 therapy; cancer diagnosis; cellular imaging; clinically relevant; cohort; exhaust; genetic signature; immune checkpoint blockade; immunopathology; immunotherapy trials; improved; insight; ipilimumab; multiple omics; novel; peripheral blood; phase II trial; programmed cell death ligand 1; protein expression; response; single cell sequencing; tumor; tumor microenvironment; viral DNA

Project Summary/Abstract Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-driven malignancy that is endemic to East and Southeast Asia. The overall 5-year survival rate for endemic NPC is only 51%, which represents an unmet clinical need. While NPC tumors are known to be infected with EBV and express PD-L1, little is known about the role of EBV-specific T cells in the control of NPC and anti-PD-1 therapy has shown a low rate of efficacy (ORR ~20%). The goal of this study is to better understand the role of EBV-specific T cell responses in NPC immunopathology and immunotherapeutic response. We will test the specific hypotheses that: 1. EBV-specific T cells contribute to tumor control elicited by combination anti-PD-1 and anti-CTLA-4 checkpoint blockade immunotherapy, and 2. that the phenotypic and clonal characteristics/dynamics of peripheral EBV-specific T cells can be useful as indicators of clinical outcomes for NPC patients. To test these hypotheses, we will leverage our access to two Singaporean NPC patient cohorts: Cohort 1. A 51-patient cohort of new-diagnosis NPC for which viably frozen PBMCs and archival FFPE tissues are available and Cohort 2. A 50-patient cohort participating in a phase II trial (NCT03097939 - National Cancer Centre Singapore) testing the combination of Ipilumimab and Nivolumimab (Ipi.+Nivo.) immunotherapy with longitudinally collected PBMCs and tissue biopsies. Recently published preliminary analysis (AACR 2020) from this clinical trial shows that combined Ipi.+Nivo. therapy is safe and achieved durable responses in recurrent and metastatic NPC patients and identified a negative association between circulating EBV-DNA levels and response. In addition, preliminary analysis of new-diagnosis NPC patient peripheral blood samples from Cohort 1 show associations between certain phenotypic profiles of CD8+ T cells and clinical parameters such as EBV-DNA levels. Therefore, in Aim 1. we will investigate the clinical relevance of these preliminarily identified NPC-associated CD8+ T cell phenotypes. In addition to in-depth single cell transcriptional, functional TCR sequence profiling of these cells, cellular imaging, transcriptional profiling and bulk TCR sequencing of patient-matched tumor will allow discovery of novel associations between peripheral T cells and the tumor microenvironment. In Aim 2., we will characterize EBV-specific T cell responses in the NPC periphery and tumor microenvironment during combination Ipi.+Nivo. immunotherapy treatment to identify novel associations between the phenotypic profiles of EBV-specific T cells and immunotherapeutic response. In Aim 3., we will investigate T cell clonal dynamics associated with treatment induced changes to the NPC-specific immune response by comparing the TCR clonal diversity in peripheral blood and tumor biopsy samples from different stages of treatment. Overall, characterization of EBV-specific T cells phenotypes in the NPC periphery and the tumor using multiple cutting-edge approaches will not only improve our understanding of the NPC immune landscape, but also potentially identify clinically relevant EBV-specific T cell phenotypes that could be tested in future NPC immunotherapy trials.

项目摘要/摘要 鼻咽癌（NPC）是爱泼斯坦 - 巴尔病毒（EBV）驱动的恶性肿瘤，是东方和东方特有的 东南亚。流行NPC的总体5年生存率仅为51％，这代表了未完成的临床 需要。虽然已知NPC肿瘤感染EBV和Express PD-L1，但对 NPC和抗PD-1治疗的EBV特异性T细胞在疗效率较低（ORR〜20％）中。 这项研究的目的是更好地了解EBV特异性T细胞反应在NPC免疫病理学中的作用 和免疫治疗反应。我们将测试特定假设：1。EBV特异性T细胞有助于 肿瘤对照组合通过抗PD-1和抗CTLA-4检查点阻断免疫疗法引起，2。 外周EBV特异性T细胞的表型和克隆特征/动力学可以用作 NPC患者的临床结局指标。为了检验这些假设，我们将利用对两个假设的访问 新加坡NPC患者队列：队列1。新诊断NPC的51名患者队列，可通过冻结 可以使用PBMC和档案FFPE组织，并提供队列2。 试验（NCT03097939-新加坡国家癌症中心）测试ipilumimab和 Nivolumimab（IPI。+Nivo。）纵向收集的PBMC和组织活检的免疫疗法。最近 该临床试验的发表初步分析（AACR 2020）表明，IPI+Nivo结合了。治疗是安全的 并在复发和转移性NPC患者中实现了持久的反应，并确定了负相关性 在循环的EBV-DNA水平和响应之间。此外，新诊断NPC的初步分析 从1的患者外周血样本1显示了CD8+的某些表型谱之间的关联 T细胞和临床参数，例如EBV-DNA水平。因此，在AIM 1中。我们将研究临床 这些初步鉴定的NPC相关CD8+ T细胞表型的相关性。除了深入单曲 这些细胞的细胞转录，功能性TCR序列分析，细胞成像，转录分析和 患者匹配的肿瘤的批量TCR测序将允许发现周围T之间的新型关联 细胞和肿瘤微环境。在AIM2中，我们将表征NPC中的EBV特异性T细胞响应 IPI组合期间的周围和肿瘤微环境。免疫疗法治疗以识别新型 EBV特异性T细胞的表型特征与免疫治疗反应之间的关联。目标 3.，我们将研究与治疗引起的NPC特异性变化相关的T细胞克隆动力学 通过比较外周血和肿瘤活检样本中TCR克隆多样性的免疫反应 不同的治疗阶段。总体而言，NPC外围的EBV特异性T细胞表型的表征 使用多种尖端方法的肿瘤不仅可以提高我们对NPC的理解 免疫景观，但也有可能识别可能是的临床相关的EBV特异性T细胞表型 在未来的NPC免疫疗法试验中进行了测试。