title: Clinical and immunomodulatory effects of celecoxib plus interferon-alpha in metastatic renal cell carcinoma patients with COX-2 tumor immunostaining.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  COX-2-expressing RCC demonstrates inherent immunosuppression. COX-2 inhibition with IFN results in minimal immunomodulation and no augmented clinical activity in RCC.
authors.affiliation: Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH 44195, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Schwandt
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Garcia
authors.forename: Paul
authors.initials: P
authors.lastname: Elson
authors.forename: Jeanie
authors.initials: J
authors.lastname: Wyckhouse
authors.forename: James H
authors.initials: JH
authors.lastname: Finke
authors.forename: Joanna
authors.initials: J
authors.lastname: Ireland
authors.forename: Pierre
authors.initials: P
authors.lastname: Triozzi
authors.forename: Ming
authors.initials: M
authors.lastname: Zhou
authors.forename: Robert
authors.initials: R
authors.lastname: Dreicer
authors.forename: Brian I
authors.initials: BI
authors.lastname: Rini
mesh_terms: D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology; D000068579:Celecoxib; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000187:drug effects; D015232:Dinoprostone / Q000096:biosynthesis / Q000378:metabolism; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018417:Th1 Cells / Q000276:immunology; D058408:Th1-Th2 Balance; D018418:Th2 Cells / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D007155:Immunologic Factors; D016898:Interferon-alpha; D011720:Pyrazoles; D013449:Sulfonamides; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000068579:Celecoxib; D015232:Dinoprostone