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，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其中最重要的是配体 PD-L1 和 PD-L2。在临床上，有六种独特的 PD-(L)1 与激活的免疫细胞上的共抑制受体 PD-1 相互作用。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。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，即了解底层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 PD-L1 上调对某些肿瘤的主要机制是癌症免疫治疗的方法。结果显示不是组成型诱导而是适应性抵抗，因此肿瘤对通过 IFN-g（肿瘤细胞产生的主要细胞因子 TGF-b）“感知”免疫威胁。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，通过无偏基因鉴定出肿瘤内在耐药机制。表达谱分析成为抗 PD-(L)1 失败的关键决定因素，同时也取得了重大进展。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；以及 3) 表征免疫细胞和抗 PD(L)1 反应/耐药的基质因子预计将得到转化。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。