An infection-enhanced oncolytic adenovirus secreting H. pylori neutrophil-activating protein with therapeutic effects on neuroendocrine tumors
2013 (English)In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 21, no 11, 2008-2018 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 anti-tumor 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 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 post-virus administration. Our observations suggest that HP-NAP can serve as a potent immunomodulator in promoting anti-tumor immune response in the tumor microenvironment and enhance the therapeutic effect of oncolytic adenovirus.
Place, publisher, year, edition, pages
2013. Vol. 21, no 11, 2008-2018 p.
Helicobacter pylori, Neutrophil Activating Protein, adenovirus, cancer therapy
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject Molecular Medicine; Clinical Virology; Medical Virology; Clinical Immunology
IdentifiersURN: urn:nbn:se:uu:diva-203649DOI: 10.1038/mt.2013.153ISI: 000326937000007PubMedID: 23817216OAI: oai:DiVA.org:uu-203649DiVA: diva2:637203
FunderSwedish Cancer Society, 10‐0105Swedish Cancer Society, 10‐0552Swedish Research Council, K2013‐55X‐22191‐01‐3
De två (2) sista författarna delar sistaförfattarskapet.
Open access under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License (CC BY-NC-ND). 2013.
The Swedish Children Cancer Foundation(PROJ10/027), Gunnar Nilsson’s Cancer Foundation, Marcus and Marianne Wallenberg’sFoundation2013-07-162013-07-162016-09-30Bibliographically approved