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Role of PD-1/PDL-1 in Lung Carcinogenesis and Therapy

PD-1/PDL-1在肺癌发生和治疗中的作用

基本信息

批准号：
8706103
负责人：
BO LU
金额：
$ 16.35万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8706103
关键词：
Address Advanced Malignant Neoplasm Antigens Apoptosis Behavior Biological Markers Blocking Antibodies Cancer Biology Cancer Patient Chest Cisplatin Clinical Clinical Data Clinical Research Clinical Trials Disease Distant Dose Failure Genetic Models Human Immune Immune Tolerance Immune response Immunologic Surveillance Immunotherapeutic agent Immunotherapy Ionizing radiation Knockout Mice Ligands Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Memory Microscopic Molecular Mus Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Outcome Pathway interactions Patients Physiological Radiation Radiation Therapy Oncology Group Radiation therapy Recurrence Regimen Regulatory T-Lymphocyte Reporting Research Resistance Role Signal Transduction Source Staging T cell anergy T-Cell Activation T-Lymphocyte Testing Therapeutic Tissues Toxic effect Transgenic Mice Treatment Failure base cancer cell cancer type carcinogenesis chemoradiation chemotherapy cohort cytotoxic exhaustion improved inhibitor/antagonist lung carcinogenesis mouse model neoplastic cell novel therapeutics outcome forecast patient population prevent public health relevance receptor response standard care tumor

项目摘要

DESCRIPTION (provided by applicant): The outcomes of stage III non-small cell lung cancer seem to reach a plateau following two decades of clinical research by optimally combining cisplatin-based chemotherapy and thoracic radiotherapy. Escalation of radiotherapy dose failed to improve outcome as demonstrated by the recent RTOG 0617 trial. Frequent failures with systemic recurrence following concurrent chemoradiation contribute to disappointing cure rate of locally advanced lung cancer. Encouraging clinical data have come from recent immunotherapeutic trials. Moreover, combining radiotherapy with immunotherapy has yielded potentially synergistic systemic/abscopal (i.e. distant) effects. Molecular studies have pointed to a crucial role for immunomodulating B7-H1 or PDL-1/PD-1 pathway in the control of T cell activation and in maintaining immunotolerance induced by tumor cells. PDL-1, a ligand of PD-1 is over-expressed on human tumors from different tissue origins whereas PD-1 receptor is expressed in T cells to prevent T-cell overactivation in physiological conditions. In certain types of cancer, higher level of PDL-1 has been correlated with poor prognosis. Tumor-induced PDL-1 utilizes multiple mechanisms to evade host immune surveillance, including 1) promoting T cell anergy, exhaustion, unresponsiveness and apoptosis, 2) inducing the expansion of regulatory T cells, and 3) enhancing tumor therapeutic resistance. Four therapeutic biologics targeting the human PD-1 are currently in clinical trials, with promising results [1]. PD-1/PDL-1-blocking mAbs are being evaluated to treat various advanced cancers [2]. Recent reports on clinical trials using BMS-936558 (a PD-1 inhibitor) and BMS-936559 (a PDL-1 inhibitor) showed significant objective responses (18% among patients with non-small-cell lung cancers). The clinical response is also durable, suggesting immune memory. Tumor PDL-1 over-expression correlates with anti-tumor responses in a small patient cohort, suggesting that PDL-1 could be a potential biomarker for PD-1 inhibitors. Integrating PD-1 inhibitors into the standard chemoradiation regimens for locally advanced non-small cell lung cancer potentially breaks immune tolerance against lung cancer cells and synergistically activates T cells as cancer antigens are released following cytotoxic chemoradiation treatment. These immune responses may impact distant microscopic metastases, which are sources for treatment failures in this population of patients. We hypothesize PD-1 and PDL-1 modulate lung carcinogenesis and therapeutic response to chemotherapy and radiotherapy and combining PD-1/PDL-1 inhibitors with chemoradiation regimens improves therapeutic outcomes of lung cancer patients: Aim 1: Determine the role of PD-1 and PDL-1 in carcinogenesis and therapeutic response of lung cancer; Aim 2: Determine the efficacy and toxicities of combining PD-1 or PDL-1-blocking antibody and thoracic radiotherapy in an orthotopic mouse model of lung cancer. The proposed studies will help us to understand the role of PD-1 and PDL-1 in lung carcinogenesis and therapeutic response of lung cancer.

描述（由申请人提供）：经过20年的临床研究，通过最佳结合顺铂化疗和胸部放疗，III期非小细胞肺癌的结局似乎达到了平台期。最近的RTOG 0617试验表明，放疗剂量的增加未能改善预后。局部晚期肺癌同步放化疗后经常失败并伴有全身复发，导致其治愈率令人失望。令人鼓舞的临床数据来自最近的免疫试验。此外，将放射疗法与免疫疗法相结合已经产生了潜在的协同全身/远端（即远端）效应。分子研究表明免疫调节B7-H1或PDL-1/PD-1通路在控制T细胞活化和维持肿瘤细胞诱导的免疫耐受中的关键作用。PD-I的配体PDL-1在来自不同组织来源的人肿瘤上过表达，而PD-I受体在T细胞中表达以防止生理条件下的T细胞过度活化。在某些类型在恶性肿瘤中，PDL-1水平升高与预后不良相关。肿瘤诱导的PDL-1利用多种机制逃避宿主免疫监视，包括1）促进T细胞无反应性、耗竭、无反应性和凋亡，2）诱导调节性T细胞的扩增，和3）增强肿瘤治疗抗性。目前，四种靶向人PD-1的治疗性生物制剂正在进行临床试验，并取得了可喜的成果[1]。PD-1/PDL-1阻断mAb正在被评估用于治疗各种晚期癌症[2]。最近使用BMS-936558（PD-1抑制剂）和BMS-936559（PDL-1抑制剂）的临床试验报告显示了显著的客观缓解（非小细胞肺癌患者中为18%）。临床反应也是持久的，表明免疫记忆。肿瘤PDL-1过表达与小患者队列中的抗肿瘤反应相关，表明PDL-1可能是PD-1抑制剂的潜在生物标志物。将PD-1抑制剂整合到局部晚期非小细胞肺癌的标准放化疗方案中可能会破坏对肺癌细胞的免疫耐受，并协同激活T细胞，因为癌抗原在细胞毒性放化疗治疗后释放。这些免疫应答可能影响远处显微镜下转移，这是该患者人群治疗失败的原因。我们假设PD-1和PDL-1调节肺癌发生以及对化疗和放疗的治疗反应，并且PD-1/PDL-1抑制剂与放化疗方案的组合改善肺癌患者的治疗结果：目的1：确定PD-1和PDL-1在肺癌发生和治疗反应中的作用;目的2：在肺癌原位小鼠模型中确定PD-1或PDL-1阻断抗体与胸部放射疗法组合的功效和毒性。这些研究将有助于我们了解PD-1和PDL-1在肺癌发生和治疗反应中的作用。