Targeting an Oncolytic Influenza A Virus to Tumor Tissue by Elastase

Irina Kuznetsova, Tobias Arnold, Thomas Aschacher, Cornelia Schwager, Balazs Hegedus, Tamas Garay, Marina Stukova, Maria Pisareva, Stephan Pleschka, Michael Bergmann, Andrej Egorov

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5 Citations (Scopus)

Abstract

Oncolytic viruses are currently established as a novel type of immunotherapy. The challenge is to safely target oncolytic viruses to tumors. Previously, we have generated influenza A viruses (IAVs) containing deletions in the viral interferon antagonist. Those deletions have attenuated the virus in normal tissue but allowed replication in tumor cells. IAV entry is mediated by hemagglutinin (HA), which needs to be activated by a serine protease, for example, through trypsin. To further target the IAV to tumors, we have changed the trypsin cleavage site to an elastase cleavage site. We chose this cleavage site because elastase is expressed in the tumor microenvironment. Moreover, the exchange of the cleavage site previously has been shown to attenuate viral growth in lungs. Newly generated elastase-activated influenza viruses (AE viruses) grew to similar titers in tumor cells as the trypsin-activated counterparts (AT viruses). Intratumoral injection of AE viruses into syngeneic B16f1 melanoma-derived tumors in mice reduced tumor growth similar to AT viruses and had a better therapeutic effect in heterologous human PANC-1-derived tumors. Therefore, the introduction of the attenuation marker “elastase cleavage site” in viral HA allows for safe, effective oncolytic virus therapy.

Original languageEnglish
Pages (from-to)37-44
Number of pages8
JournalMolecular Therapy - Oncolytics
Volume7
DOIs
Publication statusPublished - Dec 15 2017

Keywords

  • influenza A virus
  • neutrophilic elastase
  • oncolytic virotherapy
  • tumor immunology

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research
  • Pharmacology (medical)

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  • Cite this

    Kuznetsova, I., Arnold, T., Aschacher, T., Schwager, C., Hegedus, B., Garay, T., Stukova, M., Pisareva, M., Pleschka, S., Bergmann, M., & Egorov, A. (2017). Targeting an Oncolytic Influenza A Virus to Tumor Tissue by Elastase. Molecular Therapy - Oncolytics, 7, 37-44. https://doi.org/10.1016/j.omto.2017.09.002