Clinical and Immunomodulatory Effects of Celecoxib Plus Interferon-Alpha in Metastatic Renal Cell Carcinoma Patients with COX-2 Tumor Immunostaining
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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.
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.
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.
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.
COX-2-expressing RCC demonstrates inherent immunosuppression. COX-2 inhibition with IFN results in minimal immunomodulation and no augmented clinical activity in RCC.
KeywordsInterferon-α celecoxib renal cell carcinoma immunotherapy T-regulatory cells