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：
DREW M. PARDOLL
金额：
$ 58.81万
依托单位：
JOHNS HOPKINS UNIVERSITY
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

来源：
https://reporter.nih.gov/project-details/10355495
关键词：
Activin Receptor Address Advanced Malignant Neoplasm Affect Aftercare Antibodies Archives Area Biological Markers Biopsy Blocking Antibodies Cancer Patient Cells Clinic Clinical Complex Core Biopsy Data Development Dinoprostone Disease Elements Enhancers Excision FDA approved Failure Formalin Foundations Funding Gene Expression Profiling Geography Head and Neck Squamous Cell Carcinoma Human Image Immune Immune system Immunofluorescence Immunologic Immunohistochemistry Immunosuppression Immunotherapeutic agent Immunotherapy In Situ In Vitro Interferon Type II Knock-in Mouse Knock-out Knowledge LRRC32 gene Laboratories Lasers Ligands Malignant Neoplasms Malignant neoplasm of lung Mediating Membrane Merkel cell carcinoma Modeling Molecular Monoclonal Antibodies Mus Nature Neoadjuvant Therapy Operative Surgical Procedures Outcome PD-1 pathway PD-1/PD-L1 PDL1 pathway PTGS2 gene Paraffin Embedding Pathologic Pathway interactions Patients Pattern Pharmaceutical Preparations Play Population Process Prostaglandin Receptor Prostaglandins RNA Regimen Regulation Regulatory Pathway Regulatory T-Lymphocyte Relapse Resistance Resolution Role Signal Pathway Signal Transduction Solid Neoplasm Specimen Structure T-Lymphocyte Technology Testing Tissue Stains Tissue imaging Tissues Transforming Growth Factor beta Translating Tumor-infiltrating immune cells Up-Regulation activin A anti-PD-1 anti-PD-L1 anti-PD1 therapy anti-tumor immune response antitumor effect base cancer immunotherapy cancer therapy cancer type cell type chemokine clinical application clinical translation combinatorial cytokine data curation imaging platform immune resistance in vivo in vivo Model in vivo evaluation individual patient inhibitor melanoma mouse model neoplastic cell next generation novel personalized immunotherapy pre-clinical programmed cell death ligand 1 programmed cell death protein 1 promoter receptor resistance mechanism responders and non-responders response selective expression small molecule standard of care therapy resistant transcriptome sequencing treatment response tumor tumor growth tumor microenvironment tumor-immune system interactions

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，在鼠模型和人类已经确定了细胞内信号通路和膜配体和接收器的表达局部抑制抗肿瘤免疫反应。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。在诊所中，六个独特的pd-（l）1 阻断抗体对潜水员的晚期实体瘤产生了重大影响，并且具有到目前为止，FDA批准了17种不同的疾病适应症。此外，免疫组织化学在预处理肿瘤活检中测试PD-L1表达，在我们的抗PD-1研究中相关临床反应已转化为当前在特定癌症中批准的4种不同的商业测试识别患者治疗反应可能增加的类型。当前将在本提案中解决的挑战是了解基础机制抗PD-（L）1个单个患者和癌症类型的抗性，影响约80％的患者接受这些药物。为什么许多PD-L1+肿瘤患者对PD-1途径阻滞剂没有反应？为什么要这样做一些响应者随后继电器？为什么某些肿瘤类型特别抗这种形式免疫疗法？在过去的R01资金期间，对表达的调节有了重大发现 PD-1及其配体，对识别生物标志物和开发组合具有重要意义癌症免疫疗法的方法。在某些肿瘤上上调的PD-L1上调的主要机制是揭示不是宪法诱导的，而是适应性抵抗，从而使肿瘤对通过IFN-G对免疫威胁的“感知”。相反，肿瘤细胞TGF-B产生的主要细胞因子为证明可以增强TCR驱动的PD-1启动子活性，从而增强T细胞上的PD-1表达，相关的分子GARP和1C型激活素受体在维持Treg中起关键作用 TME中的免疫抑制。最后，通过无偏基因鉴定的肿瘤内部抗性机制表达分析出现为抗PD-（L）1失败的关键决定剂。同时，显着进步在具有所谓的“ Astropath”平台的多维组织成像中，我们的能力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。这种竞争的更新将通过解决三个来表征抗PD-（l）1肿瘤的性质目的：1）在Pd-（l）1非反应者中选择性地识别Treg分子； 2）定义肿瘤介导抗PD-（l）1电阻的细胞中心途径； 3）特征是免疫电池和抗PD（L）1响应/电阻的基质因子。这些研究预计会翻译进入新的生物标志物和治疗组合的发展，提高了抗PD-（L）1的效率。