Novel COX-2 and PGE2-dependent pathways in lung cancer

描述(申请人提供)：尽管对传统疗法进行了重点研究，但肺癌的五年存活率仍然只有14%，在过去的25年里只有很小的改善。这些令人沮丧的统计数据引导我们探索肺癌诱导的免疫抑制环境，并基于这一新知识开发新的靶向治疗。肿瘤反应性T细胞已被证明在肺癌组织中积聚，但没有反应。事实上，非小细胞肺癌(NSCLC)的肿瘤浸润性淋巴细胞(TIL)中有很高比例是CD4+CD25hi9h T调节(T Reg)细胞。在以前的研究中，我们发现在非小细胞肺癌中存在一个免疫抑制网络，这是由于肿瘤环氧合酶-2(COX-2)过表达所致。目前的建议特别关注确定COX-2及其代谢物前列腺素E2(PGE2)通过促进T调节细胞活性抑制肺癌免疫反应的途径。其具体目的是：1)确定COX-2/PGE2对T细胞功能的调节作用。我们将确定COX-2和PGE2在体外调节人类T细胞功能活性的途径，以及2)确定COX-2抑制对NSCLC中T调节细胞的影响两项先导性研究将在晚期和可手术切除的疾病患者中进行。在第一项研究中，我们将进行一项双中心、非随机、剂量递增的I期临床试验，以评估COX-2抑制对NIB和IV期NSCLC患者T调节细胞的影响。我们将24名受试者纳入三个递增剂量队列，以确定塞来昔布降低晚期非小细胞肺癌患者T细胞的最佳生物剂量(OBD)。第二项初步研究将评估早期、可切除的非小细胞肺癌患者。40名符合条件的受试者将被随机分配到上文确定的产科疾病中心接受塞来昔布治疗，或在手术切除前7天内不接受干预。这些研究的总体目标是确定COX-2和PGE2抑制在非小细胞肺癌CD4+CD25高T调节(T Reg)细胞调节中的作用。

DESCRIPTION (provided by applicant): Despite focused research in conventional therapies, the five-year survival rate for lung cancer remains only 14 percent and has improved only minimally in the past 25 years. These dismal statistics have led us to explore the lung cancer-induced immunosuppressive environment and to develop novel targeted therapies based on this new knowledge. Tumor-reactive T cells have been shown to accumulate in lung cancer tissues but fail to respond. In fact, a high proportion of non-small cell lung cancer (NSCLC) tumor-infiltrating lymphocytes (TIL) are CD4+CD25hi9h T regulatory (T reg) cells. In previous studies we found an immune suppressive network in NSCLC that is due to overexpression of tumor cyclooxygenase 2 (COX-2). The current proposal focuses particular attention on defining the pathways whereby the COX-2 and its metabolite prostaglandin E2 (PGE2) inhibit immune responses in lung cancer by promoting T regulatory cell activity. The specific aims will: 1) determine the role of COX-2/PGE2-dependent modulation of T reg cell function. We will determine the pathways whereby COX-2 and PGE2 modulate human T reg cell functional activity in vitro and 2) determine the effect of COX-2 inhibition on T regulatory cells in NSCLC two pilot studies will be conducted in patients with advanced and surgically resectable disease. In the first study, we will conduct a two-center, non-randomized, dose-escalation phase I clinical trial to evaluate the effects of COX-2 inhibition on T regulatory cells in stage NIB and IV NSCLC patients. We will enroll 24 subjects in three escalating dose-cohorts to establish the optimal biologic dose (OBD) of celecoxib for decreasing T reg cells in advanced NSCLC. The second pilot study will evaluate subjects with early stage, resectable NSCLC. Forty eligible subjects will be randomly assigned to receive celecoxib at the OBD determined above or no intervention for a 7-day period prior to surgical resection. The overall goal of these studies is to determine the role of COX-2 and PGE2 inhibition in modulation of CD4+CD25high T regulatory (T reg) cells in NSCLC.