5116 Background: Cyclooxygenase-2 (COX-2) has been correlated with RCC stage and grade, and overexpression can lead to dysregulation of dendritic cells (DC) and CD4+/CD25+/FOXP3+ regulatory T cells (Treg). A previous trial of celecoxib in combination with IFNα2b in RCC (Rini et al, Cancer. 2006) demonstrated an association between more intense COX-2 RCC tumor staining and clinical response. METHODS Pts with cytokine-naïve mRCC with at least 10% maximal COX-2 tumor staining received IFNα2b MU five times/week plus celecoxib 400 mg BID continuously. Baseline tumor tissue was stained for COX-2, CD4+ and CD8+ T cells, Treg and DC (s100 and CD208). Peripheral blood prostaglandin E2 (PGE2), DC and Treg number/function and intracellular T cell cytokine production were measured at baseline, at the end of cycles 2 and 4 and at end of treatment. Activation of DC was assessed by IL-12 and IL-10 mRNA and protein production by ELISA. The primary endpoint was objective response rate (ORR). Secondary endpoints were DC / Treg number and cytokine production changes with therapy. The trial tested a null hypothesis of ORR <20% vs. alternative hypothesis of ORR >40%; beta = 0.8 and alpha = 0.05 (n = 34). Immune parameters were analyzed using non-parametric methods. RESULTS Fourteen pts have been enrolled; 79% male, median age 62 (range, 43-74) and 64% ECOG performance status 0. All pts had prior nephrectomy and 36% had received prior tyrosine kinase inhibitors (TKI); MSKCC Risk Group was favorable 14%, intermediate 71%, and unfavorable 14%. The ORR was 21% and 69% of pts experienced tumor shrinkage. Median PFS is 4.4 months. Toxicity was as expected for IFN therapy. Baseline 3+ COX-2 staining was associated with elevated peripheral blood PGE2 levels (p = 0.02), reduced DC IL-12 expression (p = 0.04) and reduction in IFN gamma-producing CD3+CD4+ T-cells (p = 0.04) compared to a control group of RCC pts with <10% 3+ COX-2 staining (n = 21). No significant changes in immunomodulatory cells were observed with therapy. CONCLUSIONS COX-2 inhibition in combination with IFNα2b in maximal COX-2-expressing mRCC pts has clinical activity. COX-2 RCC tumor expression promotes an immunosuppressive phenotype. [Table: see text].