PD-1/PD-L1 modulation in cancer therapy

癌症治疗中的 PD-1/PD-L1 调节

基本信息

  • 批准号:
    10355495
  • 负责人:
  • 金额:
    $ 58.81万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-06-21 至 2026-02-28
  • 项目状态:
    未结题

项目摘要

Over the past decade, studies of the immune microenvironment of cancer in both murine models and humans has identified intracellular signaling pathways and expression of membrane ligands and receptors that locally inhibit antitumor immune responses. Among the most important are the ligands PD-L1 and PD-L2 that interact with the co-inhibitory receptor PD-1 on activated immune cells. In the clinic, six unique PD-(L)1 blocking antibodies have had significant impact against a diverse range of advanced solid tumors, and have so far been approved by the FDA for 17 different disease indications. Furthermore, immunohistochemistry testing for PD-L1 expression in pretreatment tumor biopsies, correlated in our early studies with anti-PD-1 clinical response, has been translated into 4 different commercial tests currently approved in specific cancer types to identify patients with an increased likelihood of treatment response. The current challenge, which will be addressed in this proposal, is to understand mechanisms underlying anti-PD-(L)1 resistance in individual patients and across cancer types, affecting ~80% of patients receiving these drugs. Why do many patients with PD-L1+ tumors NOT respond to PD-1 pathway blockers? Why do some responders subsequently relapse? Why are some tumor types particularly resistant to this form of immunotherapy? During the past R01 funding period, major discoveries were made regarding regulation of the expression of PD-1 and its ligands, having important implications for identifying biomarkers and developing combinatorial approaches to cancer immunotherapy. A dominant mechanism for PD-L1 upregulation on certain tumors was revealed as not being constitutive induction but rather adaptive resistance, whereby tumors respond to “sensing” of immune threat through IFN-g. Conversely, a major cytokine produced by tumor cells, TGF-b, was shown to enhance TCR-driven PD-1 promoter activity and thus PD-1 expression on T cells, and the associated molecules GARP and Activin receptor type 1C were revealed to play pivotal roles in sustaining Treg immunosuppression in the TME. Finally, tumor-intrinsic resistance mechanisms identified by unbiased gene expression profiling emerged as critical determinants of anti-PD-(L)1 failure. In parallel, significant advances in multi-dimensional tissue imaging with the so-called “AstroPath” platform have revolutionized our ability to interrogate the TME, by capturing and analyzing spatially annotated quantitative data. This competing renewal will characterize the nature of anti-PD-(L)1 tumor resistance by addressing three Aims: 1) Identify Treg molecules selectively expressed in PD-(L)1 non-responders; 2) Define tumor cell-intrinsic pathways mediating anti-PD-(L)1 resistance; and 3) Characterize immune cell and stromal factors underlying anti-PD(L)1 response/resistance. These studies are anticipated to translate into the development of new biomarkers and treatment combinations, enhancing the efficacy of anti-PD-(L)1.
在过去的十年中,对小鼠模型和癌症免疫微环境的研究 人类已经确定了细胞内信号传导途径以及膜配体和受体的表达 局部抑制抗肿瘤免疫反应。其中最重要的是配体 PD-L1 和 PD-L2 与激活的免疫细胞上的共抑制受体 PD-1 相互作用。在临床上,六种独特的PD-(L)1 阻断抗体对多种晚期实体瘤产生了显着影响,并且 迄今为止已获得 FDA 批准用于 17 种不同的疾病适应症。此外,免疫组化 测试治疗前肿瘤活检中的 PD-L1 表达,在我们的早期研究中与抗 PD-1 相关 临床反应,已转化为目前批准用于特定癌症的 4 种不同的商业测试 类型来识别治疗反应可能性增加的患者。 本提案将解决当前的挑战,即了解潜在的机制 个体患者和各种癌症类型中的抗 PD-(L)1 耐药性影响了约 80% 的接受治疗的患者 这些药物。为什么许多 PD-L1+ 肿瘤患者对 PD-1 通路阻断剂没有反应?为什么这样做 一些反应者随后复发?为什么某些肿瘤类型对这种形式特别耐药 免疫疗法? 在过去的R01资助期间,在表达的监管方面取得了重大发现 PD-1 及其配体的研究,对于识别生物标志物和开发组合具有重要意义 癌症免疫治疗的方法。某些肿瘤上 PD-L1 上调的主要机制是 研究表明,这不是组成型诱导,而是适应性抵抗,即肿瘤对 通过 IFN-g“感知”免疫威胁。相反,肿瘤细胞产生的主要细胞因子 TGF-b 是 显示增强 TCR 驱动的 PD-1 启动子活性,从而增强 T 细胞上的 PD-1 表达,以及相关的 分子 GARP 和激活素受体 1C 型被揭示在维持 Treg 中发挥关键作用 TME 中的免疫抑制。最后,通过无偏基因识别肿瘤内在耐药机制 表达谱成为抗 PD-(L)1 失败的关键决定因素。与此同时,重大进展 使用所谓的“AstroPath”平台进行多维组织成像彻底改变了我们的能力 通过捕获和分析空间注释的定量数据来询问 TME。 这种竞争性的更新将通过解决三个问题来表征抗 PD-(L)1 肿瘤耐药性的本质: 目的:1) 鉴定在 PD-(L)1 无应答者中选择性表达的 Treg 分子; 2)定义肿瘤 介导抗 PD-(L)1 耐药性的细胞内在途径; 3) 表征免疫细胞和 抗 PD(L)1 反应/抵抗的基质因子。这些研究预计将转化为 致力于开发新的生物标志物和治疗组合,增强抗 PD-(L)1 的疗效。

项目成果

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DREW M. PARDOLL其他文献

DREW M. PARDOLL的其他文献

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{{ truncateString('DREW M. PARDOLL', 18)}}的其他基金

Role of YAP in Treg Function and YAP Targeting for Cancer Immunotherapy
YAP 在 Treg 功能中的作用和 YAP 靶向癌症免疫治疗
  • 批准号:
    10547779
  • 财政年份:
    2018
  • 资助金额:
    $ 58.81万
  • 项目类别:
Role of YAP in Treg Function and YAP Targeting for Cancer Immunotherapy
YAP 在 Treg 功能中的作用和 YAP 靶向癌症免疫治疗
  • 批准号:
    10330418
  • 财政年份:
    2018
  • 资助金额:
    $ 58.81万
  • 项目类别:
E3 ligase mediated control of Foxp3 expression and immune suppression-mechanisms and potential as immunotherapeutic target
E3连接酶介导的Foxp3表达和免疫抑制机制的控制以及作为免疫治疗靶点的潜力
  • 批准号:
    10331033
  • 财政年份:
    2018
  • 资助金额:
    $ 58.81万
  • 项目类别:
The Role of EOS in Regulatory T-cell Biology.
EOS 在调节性 T 细胞生物学中的作用。
  • 批准号:
    8490291
  • 财政年份:
    2010
  • 资助金额:
    $ 58.81万
  • 项目类别:
Mechanisms of TH17 Inflammation-Induced Colon Carcihogenesis
TH17炎症诱导的结肠癌发生机制
  • 批准号:
    8657874
  • 财政年份:
    2010
  • 资助金额:
    $ 58.81万
  • 项目类别:
The Role of EOS in Regulatory T-cell Biology.
EOS 在调节性 T 细胞生物学中的作用。
  • 批准号:
    8683077
  • 财政年份:
    2010
  • 资助金额:
    $ 58.81万
  • 项目类别:
Mechanisms of TH17 Inflammation-Induced Colon Carcihogenesis
TH17炎症诱导的结肠癌发生机制
  • 批准号:
    8105255
  • 财政年份:
    2010
  • 资助金额:
    $ 58.81万
  • 项目类别:
Enterotoxigenic Bacteroides fragilis: A bacterial promoter of colon oncogenesis
产肠毒素脆弱拟杆菌:结肠癌发生的细菌启动子
  • 批准号:
    8707985
  • 财政年份:
    2010
  • 资助金额:
    $ 58.81万
  • 项目类别:
PD-1/PD-L1 modulation in cancer therapy
癌症治疗中的 PD-1/PD-L1 调节
  • 批准号:
    9188057
  • 财政年份:
    2010
  • 资助金额:
    $ 58.81万
  • 项目类别:
Enterotoxigenic Bacteroides fragilis: A bacterial promoter of colon oncogenesis
产肠毒素脆弱拟杆菌:结肠癌发生的细菌启动子
  • 批准号:
    8137121
  • 财政年份:
    2010
  • 资助金额:
    $ 58.81万
  • 项目类别:

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