Celecoxib has potent antitumour effects as a single agent and in combination with BCG immunotherapy in a model of urothelial cell carcinoma

Objectives: Prostaglandin E-2 (PGE(2)) is a potent immune modulator and known to suppress both tumour antigen-specific helper T (T(H)1) cells and the generation of cytotoxic T lymphocytes (CTLs). We hypothesised that a combination of the cyclooxygenase 2 (COX-2) selective inhibitor celecoxib and intravesical bacillus Calmette-Guerin (BCG), an effective tumour immunoprophylaxis and ablative therapy for non-muscle-invasive bladder cancer, would be more effective than BCG alone. Methods: We assessed urinary levels of PGE(2) in humans receiving BCG and in a murine model of urothelial cell carcinoma (UCC). The cytokine response to BCG plus celecoxib was assessed in murine dendritic cells (DCs) in vitro and tumour ablation was assessed in an orthotopic MBT2 murine bladder cancer model. Results: Administration of intravesical BCG resulted in elevated urinary PGE(2) levels in patients with high-grade superficial UCC and in a mouse model of UCC. in vitro, activation of DCs with BCG stimulated COX-2 up-regulation and release of the archetypal tolerogenic factors, PGE(2) and interleukin 10. In a superficial mouse model of UCC, combination of celecoxib and intravesical BCG therapy resulted in increased tumour infiltration of CD4(+) T cells and improved efficacy when compared to BCG alone. Further, celecoxib demonstrated marked antitumour efficacy when administered in the absence of BCG immunotherapy. Conclusions: This study demonstrates that a combination strategy involving BCG immunotherapy and celecoxib may be more therapeutically beneficial than stand-alone intravesical therapy. (C) 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.