Clinical and immunomodulatory effects of celecoxib plus Interferon-Alpha in Metastatic Renal Cell Carcinoma patients with COX-2 tumor immunostaining

Anita Schwandt, Jorge A. Garcia, Paul Elson, Jeanie Wyckhouse, James H. Finke, Joanna Ireland, Pierre Triozzi, Ming Zhou, Robert Dreicer, Brian I. Rini

Research output: Contribution to journalArticle

13 Citations (Scopus)

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-a 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-a 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.

Original languageEnglish (US)
Pages (from-to)690-698
Number of pages9
JournalJournal of Clinical Immunology
Volume31
Issue number4
DOIs
StatePublished - Aug 1 2011

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Celecoxib
Renal Cell Carcinoma
Interferon-alpha
Dinoprostone
Staining and Labeling
Neoplasms
Immunomodulation
Cell- and Tissue-Based Therapy
Immunosuppression
Interferons
Immunohistochemistry
Confidence Intervals
Cytokines

Keywords

  • Celecoxib
  • Immunotherapy
  • Interferon-α
  • Renal cell carcinoma
  • T-regulatory cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Clinical and immunomodulatory effects of celecoxib plus Interferon-Alpha in Metastatic Renal Cell Carcinoma patients with COX-2 tumor immunostaining. / Schwandt, Anita; Garcia, Jorge A.; Elson, Paul; Wyckhouse, Jeanie; Finke, James H.; Ireland, Joanna; Triozzi, Pierre; Zhou, Ming; Dreicer, Robert; Rini, Brian I.

In: Journal of Clinical Immunology, Vol. 31, No. 4, 01.08.2011, p. 690-698.

Research output: Contribution to journalArticle

Schwandt, A, Garcia, JA, Elson, P, Wyckhouse, J, Finke, JH, Ireland, J, Triozzi, P, Zhou, M, Dreicer, R & Rini, BI 2011, 'Clinical and immunomodulatory effects of celecoxib plus Interferon-Alpha in Metastatic Renal Cell Carcinoma patients with COX-2 tumor immunostaining', Journal of Clinical Immunology, vol. 31, no. 4, pp. 690-698. https://doi.org/10.1007/s10875-011-9530-x
Schwandt, Anita ; Garcia, Jorge A. ; Elson, Paul ; Wyckhouse, Jeanie ; Finke, James H. ; Ireland, Joanna ; Triozzi, Pierre ; Zhou, Ming ; Dreicer, Robert ; Rini, Brian I. / Clinical and immunomodulatory effects of celecoxib plus Interferon-Alpha in Metastatic Renal Cell Carcinoma patients with COX-2 tumor immunostaining. In: Journal of Clinical Immunology. 2011 ; Vol. 31, No. 4. pp. 690-698.
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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-a 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-a 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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AU - Schwandt, Anita

AU - Garcia, Jorge A.

AU - Elson, Paul

AU - Wyckhouse, Jeanie

AU - Finke, James H.

AU - Ireland, Joanna

AU - Triozzi, Pierre

AU - Zhou, Ming

AU - Dreicer, Robert

AU - Rini, Brian I.

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N2 - 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-a 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-a 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.

AB - 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-a 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-a 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.

KW - Celecoxib

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KW - Interferon-α

KW - Renal cell carcinoma

KW - T-regulatory cells

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