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

描述(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射治疗的最佳组合，III期非小细胞肺癌的结果似乎达到了平台期。正如最近的RTOG 0617试验所表明的那样，提高放射治疗剂量并没有改善结果。同步放化疗后频繁的失败和全身复发导致局部晚期肺癌的治愈率令人失望。最近的免疫治疗试验提供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协同全身/远距离(即远距离)效应。分子研究指出 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起关键作用。PD-1的配体PDL-1在不同组织来源的肿瘤组织中高表达，而PD-1受体则在T细胞中表达，以防止T细胞在生理条件下过度激活。在某些类型中 在癌症中，PDL-1水平较高与预后不良相关。肿瘤诱导的PDL-1利用多种机制逃避宿主的免疫监视，包括1)促进T细胞无能、衰竭、无应答和凋亡，2)诱导调节性T细胞的扩张，3)增强肿瘤的治疗抵抗。四种针对人类PD-1的治疗性生物制剂目前正在进行临床试验，结果令人振奋[1]。PD-1/PDL-1阻断单抗正在被评估用于治疗各种晚期癌症[2]。最近关于使用bms-936558(一种PD-1抑制剂)和bms-936559(一种pdl-1抑制剂)的临床试验报告显示有显著的客观反应(在非小细胞肺癌患者中有18%)。临床反应也是持久的，表明免疫记忆。在一小部分患者队列中，肿瘤PDL-1的过度表达与抗肿瘤反应相关，这表明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，可能会打破对肺癌细胞的免疫耐受，并在细胞毒性放化疗后释放癌症抗原时协同激活T细胞。这些免疫反应可能会影响远处的微观转移，这是这群患者治疗失败的根源。我们假设PD-1和PDL-1调节肺癌的发生和对化疗和放疗的治疗反应，并联合PD-1/PDL-1抑制剂和放化疗方案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：确定PD-1或PDL-1阻断抗体联合胸部放疗在小鼠原位肺癌模型中的疗效和毒性。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。

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.