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: 10457484
• 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/10457484
• 关键词: Adoptive Immunotherapy; Aftercare; American Association of Cancer Research; Archives; Biopsy; Biopsy Specimen; Blood; Blood specimen; CD8-Positive T-Lymphocytes; Cancer Center; Cells; Characteristics; Clinical; Clinical Trials; Clone Cells; Cohort Analysis; 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 response; Immunohistochemistry; Immunologic Surveillance; Immunologics; Immunotherapeutic agent; Immunotherapy; Lymphocyte; Malignant Neoplasms; Mediating; Memory; Methods; Nasopharynx Carcinoma; Outcome; Participant; Patients; Pattern; Peptide/MHC Complex; Peripheral; Peripheral Blood Mononuclear Cell; Persons; Phase II Clinical Trials; Phenotype; Population; Prevalence; Publishing; Recurrence; Role; Sampling; Singapore; 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; base; 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.

项目总结/文摘