An infection-enhanced oncolytic adenovirus secreting H. pylori neutrophil-activating protein with therapeutic effects on neuroendocrine tumors

Mol Ther. 2013 Nov;21(11):2008-18. doi: 10.1038/mt.2013.153. Epub 2013 Jul 2.

Abstract

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-[Δ24-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)-α and MIP2-α 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics*
  • Adenoviridae / metabolism
  • Animals
  • Bacterial Proteins / genetics
  • Bacterial Proteins / immunology
  • Bacterial Proteins / therapeutic use*
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Cytokines / metabolism
  • Female
  • Genetic Therapy
  • Genetic Vectors
  • Humans
  • Mice
  • Mice, Nude
  • Neuroendocrine Tumors / immunology
  • Neuroendocrine Tumors / therapy*
  • Neutrophils / drug effects
  • Neutrophils / metabolism
  • Oncolytic Virotherapy
  • Oncolytic Viruses / genetics*
  • Oncolytic Viruses / metabolism
  • Recombination, Genetic
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology
  • Virulence Factors / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Bacterial Proteins
  • Cytokines
  • Virulence Factors
  • neutrophil-activating protein A, Helicobacter pylori