VEGF blockade enables oncolytic cancer virotherapy in part by modulating intratumoral myeloid cells

Mark A. Currier, Francis K. Eshun, Allyson Sholl, Artur Chernoguz, Kelly Crawford, Senad Divanovic, Louis Boon, William F. Goins, Jason S. Frischer, Margaret H. Collins, Jennifer L. Leddon, William H. Baird, Amy Haseley, Keri A. Streby, Pin Yi Wang, Brett W. Hendrickson, Rolf A. Brekken, Balveen Kaur, David Hildeman, Timothy P. Cripe

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Understanding the host response to oncolytic viruses is important to maximize their antitumor efficacy. Despite robust cytotoxicity and high virus production of an oncolytic herpes simplex virus (oHSV) in cultured human sarcoma cells, intratumoral (ITu) virus injection resulted in only mild antitumor effects in some xenograft models, prompting us to characterize the host inflammatory response. Virotherapy induced an acute neutrophilic infiltrate, a relative decrease of ITu macrophages, and a myeloid cell-dependent upregulation of host-derived vascular endothelial growth factor (VEGF). Anti-VEGF antibodies, bevacizumab and r84, the latter of which binds VEGF and selectively inhibits binding to VEGF receptor-2 (VEGFR2) but not VEGFR1, enhanced the antitumor effects of virotherapy, in part due to decreased angiogenesis but not increased virus production. Neither antibody affected neutrophilic infiltration but both partially mitigated virus-induced depletion of macrophages. Enhancement of virotherapy-mediated antitumor effects by anti-VEGF antibodies could largely be recapitulated by systemic depletion of CD11b + cells. These data suggest the combined effect of oHSV virotherapy and anti-VEGF antibodies is in part due to modulation of a host inflammatory reaction to virus. Our data provide strong preclinical support for combined oHSV and anti-VEGF antibody therapy and suggest that understanding and counteracting the innate host response may help enable the full antitumor potential of oncolytic virotherapy.

Original languageEnglish (US)
Pages (from-to)1014-1023
Number of pages10
JournalMolecular Therapy
Volume21
Issue number5
DOIs
StatePublished - May 2013

ASJC Scopus subject areas

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

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