title: VEGF blockade enables oncolytic cancer virotherapy in part by modulating intratumoral myeloid cells.
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.
authors.affiliation: Divison of Oncology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Currier
authors.forename: Francis K
authors.initials: FK
authors.lastname: Eshun
authors.forename: Allyson
authors.initials: A
authors.lastname: Sholl
authors.forename: Artur
authors.initials: A
authors.lastname: Chernoguz
authors.forename: Kelly
authors.initials: K
authors.lastname: Crawford
authors.forename: Senad
authors.initials: S
authors.lastname: Divanovic
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.forename: William F
authors.initials: WF
authors.lastname: Goins
authors.forename: Jason S
authors.initials: JS
authors.lastname: Frischer
authors.forename: Margaret H
authors.initials: MH
authors.lastname: Collins
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Leddon
authors.forename: William H
authors.initials: WH
authors.lastname: Baird
authors.forename: Amy
authors.initials: A
authors.lastname: Haseley
authors.forename: Keri A
authors.initials: KA
authors.lastname: Streby
authors.forename: Pin-Yi
authors.initials: PY
authors.lastname: Wang
authors.forename: Brett W
authors.initials: BW
authors.lastname: Hendrickson
authors.forename: Rolf A
authors.initials: RA
authors.lastname: Brekken
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
authors.forename: David
authors.initials: D
authors.lastname: Hildeman
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Cripe
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology; D000068258:Bevacizumab; D039481:CD11b Antigen / Q000378:metabolism; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology*; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D009389:Neovascularization, Pathologic / Q000628:therapy; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000276:immunology*; D012509:Sarcoma / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D018139:Simplexvirus / Q000276:immunology; D017154:Stromal Cells / Q000378:metabolism / Q000821:virology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D039481:CD11b Antigen; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab