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

描述（由申请人提供）：尽管对传统疗法进行了重点研究，但肺癌的五年生存率仍然只有14%，并且在过去25年中仅略有改善。这些令人沮丧的统计数据促使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累，但没有反应。事实上，高比例的非小细胞肺癌（NSCLC）肿瘤浸润淋巴细胞（TIL）是CD 4 + CD 25 hi 9 h T调节（T reg）细胞。在以前的研究中，我们发现了一个免疫抑制网络，在非小细胞肺癌是由于过度表达的肿瘤环氧合酶2（考克斯-2）。目前的建议特别关注定义的途径，其中考克斯-2和它的代谢产物前列腺素E2（PGE 2）抑制免疫反应，在肺癌通过促进T调节细胞的活性。具体的目标是：1）确定T reg细胞功能的考克斯-2/PGE 2依赖性调节的作用。我们将确定考克斯-2和PGE 2在体外调节人T reg细胞功能活性的途径和2）确定考克斯-2抑制对NSCLC中T调节细胞的影响。两项初步研究将在晚期和手术可切除疾病患者中进行。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，以评估考克斯-2抑制剂对NIB和IV期NSCLC患者T调节细胞的影响。我们将在3个递增剂量队列中招募24例受试者，以确定塞来昔布降低晚期NSCLC患者T reg细胞的最佳生物剂量（OBD）。第二项初步研究将评价早期可切除NSCLC受试者。40例合格受试者将被随机分配在上述确定的OBD接受塞来昔布治疗或在手术切除前7天内不进行干预。这些研究的总体目标是确定考克斯-2和PGE 2抑制在NSCLC中调节CD 4 + CD 25高T调节（T reg）细胞中的作用。

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.