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

• 批准号: 8567623
• 负责人: BO LU
• 金额: $ 20.23万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8567623
• 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

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，以顺铂为基础的化疗和胸部放疗的最佳组合，III期非小细胞肺癌的结果似乎达到了平台期。最近的RTOG 0617试验表明，放疗剂量的增加未能改善预后。局部晚期肺癌的治愈率令人失望。最近的免疫治疗试验取得了令人鼓舞的临床数据。此外，放射治疗与免疫治疗相结合产生了潜在的全身/体外（即远处）协同效应。分子研究指出