title: Expression of immunomodulatory neutrophil-activating protein of Helicobacter pylori enhances the antitumor activity of oncolytic measles virus.
abstract: Helicobacter pylori neutrophil-activating protein (NAP) is a major virulence factor and powerful inducer of inflammatory reaction and Th1-polarized immune response. Here, we evaluated the therapeutic efficacy of measles virus (MV) strains engineered to express secretory NAP forms against metastatic breast cancer. Recombinant viruses encoding secretory NAP forms (MV-lambda-NAP and MV-s-NAP) efficiently infect and destroy breast cancer cells by cell-to-cell viral spread and large syncytia formation independently of hormone receptor status. Intrapleural administration of MV-s-NAP doubled the median survival in a pleural effusion xenograft model: 65 days as compared to 29 days in the control group (P < 0.0001). This therapeutic effect correlated with a brisk Th1 type cytokine response in vivo. Secretory NAP was expressed at high levels by infected tumor cells and increased tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-12/23 cytokine concentrations were detected in the pleural effusion. In an aggressive model of lung metastatic breast cancer, MV-lambda-NAP and MV-s-NAP also significantly improved survival of the treated animals (P < 0.05) as compared to the control MV strain. These data suggest that potent immunomodulators of bacterial origin, such as H. pylori NAP, can enhance the antitumor effect of oncolytic viruses and support the feasibility and potential of a combined viroimmunotherapy approach.
authors.affiliation: Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA.
authors.forename: Ianko D
authors.initials: ID
authors.lastname: Iankov
authors.forename: Cory
authors.initials: C
authors.lastname: Allen
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Federspiel
authors.forename: Rae M
authors.initials: RM
authors.lastname: Myers
authors.forename: Kah Whye
authors.initials: KW
authors.lastname: Peng
authors.forename: James N
authors.initials: JN
authors.lastname: Ingle
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Russell
authors.forename: Evanthia
authors.initials: E
authors.lastname: Galanis
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D023061:Gene Order; D016480:Helicobacter pylori / Q000276:immunology; D006801:Humans; D007155:Immunologic Factors / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008459:Measles virus / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D018375:Neutrophil Activation / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D016066:Pleural Effusion, Malignant / Q000276:immunology; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
chemical_list: D001426:Bacterial Proteins; D016207:Cytokines; D007155:Immunologic Factors; D018836:Inflammation Mediators