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.

项目概要/摘要 鼻咽癌 (NPC) 是一种由 Epstein-Barr 病毒 (EBV) 驱动的恶性肿瘤，在东部和东部地区流行。 东南亚。地方性鼻咽癌的总体5年生存率仅为51%，这是一个未满足的临床目标 需要。虽然已知鼻咽癌肿瘤感染 EBV 并表达 PD-L1，但人们对 EBV 的作用知之甚少。 EBV特异性T细胞在鼻咽癌的控制和抗PD-1治疗中显示出较低的疗效（ORR~20%）。 本研究的目的是更好地了解 EBV 特异性 T 细胞反应在鼻咽癌免疫病理学中的作用 和免疫治疗反应。我们将测试以下具体假设： 1. EBV 特异性 T 细胞有助于 通过联合抗 PD-1 和抗 CTLA-4 检查点阻断免疫疗法引起肿瘤控制，以及 2. 外周 EBV 特异性 T 细胞的表型和克隆特征/动力学可用作 鼻咽癌患者的临床结果指标。为了检验这些假设，我们将利用我们对两个 新加坡鼻咽癌患者队列：队列 1。包含 51 名新诊断鼻咽癌患者的队列，对其进行活体冷冻 PBMC 和存档 FFPE 组织可用，队列 2。参与 II 期的 50 名患者队列 试验（NCT03097939 - 新加坡国家癌症中心）测试 Ipilumimab 和 Nivolumimab (Ipi.+Nivo.) 使用纵向收集的 PBMC 和组织活检进行免疫治疗。最近 该临床试验已发表的初步分析 (AACR 2020) 显示，Ipi.+Nivo 相结合。治疗是安全的 在复发性和转移性鼻咽癌患者中取得了持久的反应，并确定了负相关 循环 EBV-DNA 水平与反应之间的关系。另外，对新诊断鼻咽癌的初步分析 来自队列 1 的患者外周血样本显示 CD8+ 的某些表型特征之间存在关联 T 细胞和临床参数，例如 EBV-DNA 水平。因此，在目标 1 中，我们将研究临床 这些初步确定的 NPC 相关 CD8+ T 细胞表型的相关性。除了深入单 细胞转录、这些细胞的功能性 TCR 序列分析、细胞成像、转录分析和 对患者匹配肿瘤进行批量 TCR 测序将有助于发现外周 T 细胞之间的新关联 细胞和肿瘤微环境。在目标 2. 中，我们将描述 NPC 中 EBV 特异性 T 细胞反应的特征 Ipi.+Nivo 组合期间的外周和肿瘤微环境。免疫疗法治疗以识别新的 EBV 特异性 T 细胞的表型特征与免疫治疗反应之间的关联。瞄准 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的 TCR 克隆多样性来评估免疫反应 不同阶段的治疗。总体而言，NPC 周围 EBV 特异性 T 细胞表型的表征 对肿瘤的多种前沿手段的运用不仅会提高我们对鼻咽癌的认识 免疫景观，但也有可能识别临床相关的 EBV 特异性 T 细胞表型 在未来的 NPC 免疫治疗试验中进行了测试。