Clinical and immunomodulatory effects of celecoxib plus interferon-alpha in metastatic renal cell carcinoma patients with COX-2 tumor immunostaining.

Abstract

INTRODUCTION:

Cycloxygenase-2 (COX-2) is an enzyme involved in prostaglandin E2 (PGE(2)) 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 PGE(2) levels, and these patients demonstrated less PGE(2) 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.

• Authors: Anita Schwandt, Jorge A Garcia, Paul Elson, Jeanie Wyckhouse, James H Finke, Joanna Ireland, Pierre Triozzi, Ming Zhou, Robert Dreicer, Brian I Rini
• Journal: Journal of clinical immunology (J Clin Immunol) Vol. 31 Issue 4 Pg. 690-8 (Aug 2011) ISSN: 1573-2592 [Electronic] Netherlands
• PMID: 21487892 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Immunologic Factors
• Interferon-alpha
• Pyrazoles
• Sulfonamides
• Cyclooxygenase 2
• PTGS2 protein, human
• Celecoxib
• Dinoprostone

Topics

• Adult
• Aged
• Carcinoma, Renal Cell (drug therapy, immunology)
• Celecoxib
• Cyclooxygenase 2 (biosynthesis)
• Dendritic Cells (drug effects)
• Dinoprostone (biosynthesis, metabolism)
• Drug Therapy, Combination (adverse effects)
• Female
• Humans
• Immunologic Factors (therapeutic use)
• Interferon-alpha (administration & dosage, adverse effects, therapeutic use)
• Kidney Neoplasms (drug therapy, pathology)
• Male
• Middle Aged
• Pyrazoles (administration & dosage, adverse effects, therapeutic use)
• Sulfonamides (administration & dosage, adverse effects, therapeutic use)
• Th1 Cells (immunology)
• Th1-Th2 Balance
• Th2 Cells (immunology)
• Treatment Outcome