An infection-enhanced oncolytic adenovirus secreting H. pylori neutrophil-activating protein with therapeutic effects on neuroendocrine tumors
2013 (English)In: Mol Ther, Vol. 21, no 11, 2008-18 p.Article in journal (Refereed) Published
Helicobacter pylori neutrophil-activating protein (HP-NAP) is a major virulence factor involved in H. pylori infection. HP-NAP can mediate antitumor effects by recruiting neutrophils and inducing Th1-type differentiation in the tumor microenvironment. It therefore holds strong potential as a therapeutic gene. Here, we armed a replication-selective, infection-enhanced adenovirus with secretory HP-NAP, Ad5PTDf35-[Delta24-sNAP], and evaluated its therapeutic efficacy against neuroendocrine tumors. We observed that it could specifically infect and eradicate a wide range of tumor cells lines from different origin in vitro. Insertion of secretory HP-NAP did not affect the stability or replicative capacity of the virus and infected tumor cells could efficiently secrete HP-NAP. Intratumoral administration of the virus in nude mice xenografted with neuroendocrine tumors improved median survival. Evidence of biological HP-NAP activity was observed 24 hours after treatment with neutrophil infiltration in tumors and an increase of proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha and MIP2-alpha in the systemic circulation. Furthermore, evidence of Th1-type immune polarization was observed as a result of increase in IL-12/23 p40 cytokine concentrations 72 hours postvirus administration. Our observations suggest that HP-NAP can serve as a potent immunomodulator in promoting antitumor immune response in the tumor microenvironment and enhance the therapeutic effect of oncolytic adenovirus.
Place, publisher, year, edition, pages
2013. Vol. 21, no 11, 2008-18 p.
Adenoviridae/*genetics/metabolism, Animals, Bacterial Proteins/genetics/immunology/*therapeutic use, Cell Differentiation/drug effects, Cell Line, Tumor, Cytokines/metabolism, Female, Genetic Therapy, Genetic Vectors, Humans, Mice, Mice, Nude, Neuroendocrine Tumors/immunology/*therapy, Neutrophils/drug effects/metabolism, Oncolytic Virotherapy, Oncolytic Viruses/*genetics/metabolism, Recombination, Genetic, Tumor Microenvironment/drug effects/immunology, Virulence Factors/metabolism, Xenograft Model Antitumor Assays
IdentifiersURN: urn:nbn:se:umu:diva-110926ISBN: 1525-0024 (Electronic) 1525-0016 (Linking)OAI: oai:DiVA.org:umu-110926DiVA: diva2:865859
Ramachandran, Mohanraj Yu, Di Wanders, Alkwin Essand, Magnus Eriksson, Fredrik eng Research Support, Non-U.S. Gov't 2013/07/03 06:00 Mol Ther. 2013 Nov;21(11):2008-18. doi: 10.1038/mt.2013.153. Epub 2013 Jul 2.2015-10-292015-10-292015-10-29