Use of cyclooxygenase-2 inhibition to enhance the efficacy of immunotherapy.
Antitumor effects of cyclooxygenase-2 (COX-2) inhibition have been reported in a wide variety of tumor models and in human cancers, both as chemoprevention and therapy. Human mesothelioma tumors have been shown to overexpress COX-2 and high levels of COX-2 protein have been demonstrated to be a prognostic factor, indicating poor outcome in this tumor. In this study, we determined that inhibition of COX-2 by oral administration of Rofecoxib significantly slowed but did not cure the growth of small tumors in mesothelioma-bearing mice. Large tumors were unaffected. This effect was dependent on the presence of CD8+ T cells and was associated with increased tumor-infiltrating lymphocytes. Because these activities are consistent with a mechanism that results in a decrease in the immunosuppressive environment of the tumor, we additionally examined the effect of COX-2 blockade combined with Ad.IFN-beta therapy, a treatment that we have previously demonstrated results in expansion of antitumor CD8+ CTLs and cures a high percentage of small mesothelioma tumors in mice. Ad.IFN-beta therapy combined with COX-2 inhibition was associated with an increased number of T cells within tumors and resulted in cures of small tumors, significant inhibition of the growth of large established tumors, and inhibition of the growth of metastatic tumor foci after surgical debulking. The additive effects of these modes of treatment suggests that it would be rational to combine COX-2 inhibition with immuno- and immunogene therapy approaches (perhaps in conjunction with surgical debulking) in human clinical trials of treatment of mesothelioma and other tumors.
DeLong
Peter
P
Thoracic Oncology Laboratory, 8th Floor BRB II/III, University of Pennsylvania Medical Center, 421 Curie Boulevard, Philadelphia, PA 19104, USA. pdelong@mail.med.upenn.edu
Tanaka
Tomoyuki
T
Kruklitis
Robb
R
Henry
Adam C
AC
Kapoor
Veena
V
Kaiser
Larry R
LR
Sterman
Dan H
DH
Albelda
Steven M
SM
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003131:Combined Modality Therapy; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007783:Lactones / Q000494:pharmacology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008654:Mesothelioma / Q000201:enzymology* / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D011451:Prostaglandin-Endoperoxide Synthases; D013450:Sulfones
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D007783:Lactones; D013450:Sulfones; C116926:rofecoxib; D007371:Interferon-gamma; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases