title: Intravenous genetic mesothelin vaccine based on human adenovirus 40 inhibits growth and metastasis of pancreatic cancer.
abstract: High pancreatic cancer mortality and poor prognosis are caused by the difficulty for early diagnosis and extremely low rates of resection because of metastasis. Mesothelin overexpression in pancreatic cancer is a remarkable biomarker for tumor progression, especially for invasion and metastasis. Here, we generated a novel replication-defective recombinant adenovirus 40 (rAd40), whose gene delivery properties are totally different from a conventional rAd5. In this study, we have identified intravenous administration with rAd40 expressing mouse mesothelin (Msln) as an effective prophylactic cancer vaccine against metastatic lesions of pancreatic cancer in mice. Intravenous administration of rAd40 (rAd40 i.v.) achieved transgene delivery in wider range of organs compared to rAd5 i.v., while rAd5 was distributed mainly to the liver, spleen, and lungs. Additionally, rAd40 i.v. showed less transduction of the liver or inflammatory responses, resulted in reduced liver toxicity compared to rAd5 i.v. Also, more robust systemic antigen-specific immune responses were stimulated by rAd40 i.v. Pretreatment with a single ovalbumin-expressing rAd40 i.v. prevented tumor growth in mouse subcutaneous models of ovalbumin-expressing pancreatic cancer. When used with Msln-expressing rAd40 i.v., Msln protein expression and metastases were suppressed in a syngeneic orthotopic mouse model of pancreatic cancer, corresponding to the detection of Msln- and tumor-specific cytotoxic T lymphocyte (CTL). Our novel methods generated antitumor effects against antigen-expressing tumors through antigen- and tumor-specific CTL-mediated immunity. Thus, our results indicate that a rAd40-based intravenous vaccine provides a new strategy for the effective control of metastatic pancreatic cancer and novel therapy against other cancers and infectious diseases.
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamasaki
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Miura
authors.forename: Julia
authors.initials: J
authors.lastname: Davydova
authors.forename: Selwyn M
authors.initials: SM
authors.lastname: Vickers
authors.forename: Masato
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000260:Adenoviruses, Human / Q000145:classification / Q000276:immunology; D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D058851:GPI-Linked Proteins / Q000276:immunology*; D007275:Injections, Intravenous; D000090204:Mesothelin; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control* / Q000601:surgery; D015843:Serpins / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology
chemical_list: D019496:Cancer Vaccines; D058851:GPI-Linked Proteins; C000715527:MSLN protein, human; C000715528:Msln protein, mouse; C085344:SERPIN-B5; D015843:Serpins; D014614:Vaccines, Synthetic; C581584:rAd40; D000090204:Mesothelin