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Progression of Pancreatic Adenocarcinoma Is Significantly Impeded with a Combination of Vaccine and COX-2 Inhibition¹

Pinku Mukherjee^2,*, Gargi D. Basu, Teresa L. Tinder^*, Durai B. Subramani^*, Judy M. Bradley^*, Million Arefayene, Todd Skaar and Giovanni De Petris

^* Department of Immunology and Department of Pathology, Mayo Clinic Arizona, Scottsdale, AZ 85259; Translational Genomics Research Institute, Scottsdale, AZ 85259; and Department of Medicine, Indiana University Cancer Center, Indianapolis, IN 46202

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 KRAS^G12D 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work is supported by research grants from the National Institutes of Health (R01 CA118944; P50 CA102701) and the American Association for Cancer Research/PanCan-Pilot Award.

² Address correspondence and reprint requests to Dr. Pinku Mukherjee, Department of Biology, University of North Carolina, Charlotte, Woodward Hall, Charlotte, NC 28223. E-mail addresses: pmukherj{at}uncc.edu or mukherjee.pinku{at}mayo.edu

³ Abbreviations used in this paper: MUC1, mucin-1; IHC, immunohistochemistry; TR, tandem repeat; COX-2, cyclooxygenase-2; MSC, myeloid suppressor; Treg, T regulatory cell; PDA, pancreatic ductal adenocarcinoma; Tg, transgenic; PanIN, pancreatic intraepithelial preneoplastic lesion; DC, dendritic cell; CIS, carcinoma in situ; TDLN, tumor draining lymph node.