Progression of Pancreatic Adenocarcinoma Is Significantly Impeded with a Combination of Vaccine and COX-2 Inhibition

Abstract

With a 5-year survival rate of <5%, pancreatic cancer is one of the most rapidly fatal malignancies. Current protocols for the treatment of pancreas cancer are not as effective as we desire. In this study, we show that a novel Mucin-1 (MUC1)-based vaccine in combination with a cyclooxygenase-2 inhibitor (celecoxib), and low-dose chemotherapy (gemcitabine) was effective in preventing the progression of preneoplastic intraepithelial lesions to invasive pancreatic ductal adenocarcinomas. The study was conducted in an appropriate triple transgenic model of spontaneous pancreatic cancer induced by the KRASG12D mutation and that expresses human MUC1 as a self molecule. The combination treatment elicited robust antitumor cellular and humoral immune responses and was associated with increased apoptosis in the tumor. The mechanism for the increased immune response was attributed to the down-regulation of circulating prostaglandin E2 and indoleamine 2, 3,-dioxygenase enzymatic activity, as well as decreased levels of T regulatory and myeloid suppressor cells within the tumor microenvironment. The preclinical data provide the rationale to design clinical trials with a combination of MUC1-based vaccine, celecoxib, and gemcitabine for the treatment of pancreatic cancer.

Oncolytic Vesicular Stomatitis Virus in an Immunocompetent Model of MUC1-Positive or MUC1-Null Pancreatic Ductal Adenocarcinoma

“…KCM tumors injected with PBS as a control continued to grow at a steady rate. In agreement with previously published data demonstrating resistance of KCM tumors to gemcitabine, tumor growth with gemcitabine alone was comparable to that observed with PBS treatment (48). Treatment with VSV-⌬M51-GFP alone and VSV-⌬M51-GFP plus gemcitabine showed a statistically significant reduction in tumor burden beginning on day 12 compared to PBS treatment (Fig.…”

Inflammation restraining effects of prostaglandin E2 on natural killer–dendritic cell (NK-DC) interaction are imprinted during DC maturation

“…Our results also open the possibility to combine DC vaccination with COX2-inhibitory therapy, which has been shown previously in mouse models to enhance the efficacy of cancer vaccines. 49,50 In conclusion, we report on a novel immunosuppressive effect of PGE2, mediated by IFN-␥/FMKp-matured DCs, on NK-cell function. These current data help to understand the complex role of PGE2 in the regulation of immune responses during inflammation.…”

Inhibition of cyclooxygenase-2 enhances immunotherapy against experimental brain tumors

“…Furthermore, the evidence for PGE 2 in promoting Th1 responses has not been extracted from experimental tumor models but from delayed type hypersensitivity and autoimmune models [36,35]. In the few published reports regarding the enhanced effect of COX-2 inhibition on immunotherapy of experimental tumors, COX-2 inhibition has uniformly had an inhibitory effect on tumor growth as a single agent [17][18][19][20][21]. However, COX-2 inhibition alone, inhibition decreased the infiltration of macrophages and granulocytes into pancreatic tissue in a chronic pancreatitis rat model, whereas discontinuation restored the inflammation [37].…”

“…COX-2 is the rate-limiting enzyme of the PGE 2 synthesis. Inhibitors of COX-2 have previously been reported to boost immunotherapy against experimental non-CNS tumors [17][18][19][20][21]. Parecoxib is a selective COX-2 inhibitor used in the clinic for short-term treatment of postoperative pain and is converted to its active metabolite valdecoxib via enzymatic hydrolysis in the liver.…”