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Intrarectal Vaccination with Recombinant Vaccinia Virus Expressing Carcinoembronic Antigen Induces Mucosal and Systemic Immunity and Prevents Progression of Colorectal Cancer¹

Seunghee Kim-Schulze^*, Hong Sung Kim^*, Alberto Wainstein^*, Dae Won Kim^*, Wein Cui Yang, Dorota Moroziewicz^*, Phyllus Y. Mong^*, Michal Bereta^*, Bret Taback^*, Qin Wang^* and Howard L. Kaufman^2,*

^* The Tumor Immunology Laboratory, Division of Surgical Oncology, Columbia University, New York, NY 10032 and Division of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY 10461

The gastrointestinal mucosa contains an intact immune system that protects the host from pathogens and communicates with the systemic immune system. Absorptive epithelial cells in the mucosa give rise to malignant tumors although the interaction between tumor cells and the mucosal immune system is not well defined. The pathophysiology of colorectal cancer has been elucidated through studies of hereditary syndromes, such as familial adenomatous polyposis, a cancer predisposition syndrome caused by germline mutations in the adenomatous polyposis coli tumor suppressor gene. Patients with FAP develop adenomas and inevitably progress to invasive carcinomas by the age of 40. To better delineate the role of mucosal immunity in colorectal cancer, we evaluated the efficacy of intrarectal recombinant vaccinia virus expressing the human carcinoembryonic Ag (CEA) in a murine FAP model in which mice are predisposed to colorectal cancer and also express human CEA in the gut. Mucosal vaccination reduced the incidence of spontaneous adenomas and completely prevented progression to invasive carcinoma. The therapeutic effects were associated with induction of mucosal CEA-specific IgA Ab titers and CD8⁺ CTLs. Mucosal vaccination was also associated with an increase in systemic CEA-specific IgG Ab titers, CD4⁺ and CD8⁺ T cell responses and resulted in growth inhibition of s.c. implanted CEA-expressing tumors suggesting communication between mucosal and systemic immune compartments. Thus, intrarectal vaccination induces mucosal and systemic antitumor immunity and prevents progression of spontaneous colorectal cancer. These results have implications for the prevention of colorectal cancer in high-risk individuals.

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 was supported by NIH K08 CA79881 (to H.L.K.).

² Address correspondence and reprint requests to Dr. Howard L. Kaufman, Columbia University, 177 Fort Washington Avenue, MHB-7SK, New York, NY 10032. E-mail address: hlk2003{at}columbia.edu

³ Abbreviations used in this paper: DC, dendritic cell; FAP, familial adenomatous polyposis; Apc, adenomatous polyposis coli; CEA, carcinoembryonic Ag; IR, intrarectal; LN, lymph node; rv-CEA, recombinant vaccinia virus expressing CEA.

⁴ The online version of this article contains supplementary material.