An Infection-enhanced Oncolytic Adenovirus Secreting H. pylori Neutrophil-activating Protein with Therapeutic Effects on Neuroendocrine Tumors

• Published in: Molecular therapy 2013-11, Vol.21 (11), p.2008-2018
• Main Authors: Ramachandran, Mohanraj, Yu, Di, Wanders, Alkwin, Essand, Magnus, Eriksson, Fredrik
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Adenoviridae - metabolism; Adenoviridae/genetics/metabolism; Adenovirus; Adenoviruses; Animals; Bacterial Proteins - genetics; Bacterial Proteins - immunology; Bacterial Proteins - therapeutic use; Bacterial Proteins/genetics/immunology/therapeutic use; cancer therapy; Cell culture; Cell Differentiation - drug effects; Cell Line; Cell Line, Tumor; Clinical Immunology; Clinical Virology; Cloning; Cytokines; Cytokines - metabolism; Female; Genetic; Genetic Therapy; Genetic Vectors; Helicobacter pylori; Humans; Immunology; Infections; Klinisk immunologi; Klinisk virologi; Medical Virology; Medicinsk virologi; Mice; Mice, Nude; Molecular Medicine; Molekylär medicin; Neuroendocrine tumors; Neuroendocrine Tumors - immunology; Neuroendocrine Tumors - therapy; Neuroendocrine Tumors/immunology/therapy; Neutrophil Activating Protein; Neutrophils; Neutrophils - drug effects; Neutrophils - metabolism; Neutrophils/drug effects/metabolism; Nude; Oncolytic Virotherapy; Oncolytic Viruses - genetics; Oncolytic Viruses - metabolism; Oncolytic Viruses/genetics/metabolism; Original; Peptides; Proteins; Recombination; Recombination, Genetic; Tumor; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology; Tumor Microenvironment/drug effects/immunology; Tumor necrosis factor-TNF; Virulence; Virulence Factors - metabolism; Viruses; Xenograft Model Antitumor Assays
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1038/mt.2013.153

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.