Treg depletion-enhanced IL-2 treatment facilitates therapy of established tumors using systemically delivered oncolytic virus

Timothy Kottke, Feorillo Galivo, Phonphimon Wongthida, Rosa Maria Diaz, Jill Thompson, Dragan Jevremovic, Glen N. Barber, Geoff Hall, John Chester, Peter Selby, Kevin Harrington, Alan Melcher, Richard G. Vile

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

There are several roadblocks that hinder systemic delivery of oncolytic viruses to the sites of metastatic disease. These include the tumor vasculature, which provides a physical barrier to tumor-specific virus extravasation. Although interleukin-2 (IL-2) has been used in antitumor therapy, it is associated with endothelial cell injury, leading to vascular leak syndrome (VLS). Here, we demonstrate that IL-2-mediated VLS, accentuated by depletion of regulatory T cells (Treg), facilitates localization of intravenously (IV) delivered oncolytic virus into established tumors in immune-competent mice. IL-2, in association with Treg depletion, generates "hyperactivated" natural killer (NK) cells, possessing antitumor activity and secreting factors that facilitate virus spread/replication throughout the tumor by disrupting the tumor architecture. As a result, the combination of Treg depletion/ IL-2 and systemic oncolytic virotherapy was found to be significantly more therapeutic against established disease than either treatment alone. These data demonstrate that it is possible to combine biological therapy with oncolytic virotherapy to generate systemic therapy against established tumors.

Original languageEnglish (US)
Pages (from-to)1217-1226
Number of pages10
JournalMolecular Therapy
Volume16
Issue number7
DOIs
StatePublished - Jul 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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    Kottke, T., Galivo, F., Wongthida, P., Maria Diaz, R., Thompson, J., Jevremovic, D., Barber, G. N., Hall, G., Chester, J., Selby, P., Harrington, K., Melcher, A., & Vile, R. G. (2008). Treg depletion-enhanced IL-2 treatment facilitates therapy of established tumors using systemically delivered oncolytic virus. Molecular Therapy, 16(7), 1217-1226. https://doi.org/10.1038/mt.2008.83