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

基本信息

  • 批准号:
    10281126
  • 负责人:
  • 金额:
    $ 35.56万
  • 依托单位:
  • 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:
    2021-08-01 至 2022-03-31
  • 项目状态:
    已结题

项目摘要

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/摘要 鼻咽癌(NPC)是一种由EB病毒(EBV)驱动的恶性肿瘤, 东南亚地方性NPC的总体5年生存率仅为51%,这代表了未满足的临床 需要的虽然已知NPC肿瘤被EBV感染并表达PD-L1,但对PD-L1在NPC肿瘤中的作用知之甚少。 EBV特异性T细胞在控制NPC和抗PD-1治疗中显示出较低的疗效率(ORR ~20%)。 本研究的目的是更好地了解EB病毒特异性T细胞反应在NPC免疫病理学中的作用 和免疫反应。我们将测试的具体假设是:1。EBV特异性T细胞有助于 通过组合抗PD-1和抗CTLA-4检查点阻断免疫疗法引起的肿瘤控制,和2. 外周EBV特异性T细胞的表型和克隆特征/动力学可用作 NPC患者的临床结果指标。为了验证这些假设,我们将利用两个 新加坡NPC患者队列:队列1。51例新诊断鼻咽癌患者队列, PBMC和存档FFPE组织可用,队列2。一个50名患者的队列参与了一项II期研究, 试验(NCT 03097939-国家癌症中心新加坡)测试伊匹鲁单抗和 Nivolumimab(Ipi.+ Nivo.)使用纵向收集的PBMC和组织活检进行免疫治疗。最近 来自该临床试验的已发表的初步分析(AACR 2020)显示,Ipi.+尼沃治疗安全 并在复发和转移性NPC患者中获得持久的反应, 之间的联系。另外,对新诊断的鼻咽癌进行了初步分析, 来自队列1的患者外周血样本显示了CD 8 + T细胞的某些表型特征之间的关联。 T细胞和临床参数,如EBV-DNA水平。因此,在目标1中。我们会调查 这些初步鉴定的NPC相关CD 8 + T细胞表型的相关性。除了深入的单 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 患者匹配肿瘤的大量TCR测序将允许发现外周T细胞与肿瘤细胞之间的新关联。 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, 在组合Ipi.+期间的外周和肿瘤微环境尼沃免疫疗法治疗以鉴定新的 EBV特异性T细胞表型特征与免疫应答之间的关系。在Aim中 3.,我们将研究与治疗诱导的NPC特异性变化相关的T细胞克隆动态 通过比较外周血和肿瘤活检样品中TCR克隆多样性, 治疗的不同阶段。总体而言,NPC外周中EBV特异性T细胞表型的表征 肿瘤采用多种尖端方法不仅会提高我们对NPC的认识, 免疫景观,而且还可能鉴定临床相关的EBV特异性T细胞表型, 在未来的NPC免疫治疗试验中进行测试。

项目成果

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Evan Newell其他文献

Evan Newell的其他文献

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{{ truncateString('Evan Newell', 18)}}的其他基金

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
  • 财政年份:
    2021
  • 资助金额:
    $ 35.56万
  • 项目类别:
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:
    10601371
  • 财政年份:
    2021
  • 资助金额:
    $ 35.56万
  • 项目类别:
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
  • 财政年份:
    2021
  • 资助金额:
    $ 35.56万
  • 项目类别:

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