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

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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.