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Clinical and Immunomodulatory Effects of Celecoxib Plus Interferon-Alpha in Metastatic Renal Cell Carcinoma Patients with COX-2 Tumor Immunostaining

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Abstract

Introduction

Cycloxygenase-2 (COX-2) is an enzyme involved in prostaglandin E2 (PGE2) synthesis associated with higher renal cell carcinoma stage. COX-2 inhibition enhances interferon (IFN-α) anti-tumor immune effects in pre-clinical models. A phase II trial of celecoxib and IFN-α in a targeted population of metastatic renal cell carcinoma patients with maximal COX-2 expression was conducted.

Methods

Cytokine-naive metastatic renal cell carcinoma patients with tumors expressing ≥10% maximal COX-2 staining by immunohistochemistry received IFN-α 5 million units daily and celecoxib 400 mg orally twice daily in an open-label, single-arm phase II trial.

Results

There were 3 partial responses among 17 patients (objective response rate 18%; 95% confidence interval, 4–43%). Time to progression was 5.6 months. Increased tumor staining 3+ for COX-2 was associated with increased baseline peripheral blood PGE2 levels, and these patients demonstrated less PGE2 decrease with therapy. Patients with more 3+ COX-2 staining had significantly more CD3+ (p = 0.004) and CD4+ (p = 0.002) IFN-γ T cells at baseline and a significantly greater decrease in these cells with therapy.

Discussion

Celecoxib plus IFN-α in renal cell carcinoma (RCC) patients with maximally staining COX-2 tumors does not significantly enhance overall response rates over IFN monotherapy.

Conclusion

COX-2-expressing RCC demonstrates inherent immunosuppression. COX-2 inhibition with IFN results in minimal immunomodulation and no augmented clinical activity in RCC.

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Acknowledgment

This study was supported by NIH funding (R21CA123854 and R21CA123954). Funding for this study was provided by Merck & Co. Inc, Whitehouse Station, NJ (formerly Schering Plough Corp) and Pfizer Oncology (New York, NY).

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Correspondence to Brian I. Rini.

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Schwandt, A., Garcia, J.A., Elson, P. et al. Clinical and Immunomodulatory Effects of Celecoxib Plus Interferon-Alpha in Metastatic Renal Cell Carcinoma Patients with COX-2 Tumor Immunostaining. J Clin Immunol 31, 690–698 (2011). https://doi.org/10.1007/s10875-011-9530-x

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  • DOI: https://doi.org/10.1007/s10875-011-9530-x

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