Journal Article

VEGF Blockade Enables Oncolytic Cancer Virotherapy in Part by Modulating Intratumoral Myeloid Cells

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

2013

Overview

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.

• Publisher: Elsevier Inc,Elsevier Limited,Nature Publishing Group
• Subject: Angiogenesis / Animals / Antibodies / Antibodies, Monoclonal, Humanized - administration & dosage / Antibodies, Monoclonal, Humanized - pharmacology / Bevacizumab / Cancer / CD11b Antigen - metabolism / Cell Culture Techniques / Cell Line, Tumor / Cells / Cytokines / Cytotoxicity / Disease / Disease Models, Animal / Ewings sarcoma / Female / Genetic Vectors - administration & dosage / Genetic Vectors - immunology / Hematology / Herpes simplex virus / Herpes viruses / Hospitals / Humans / Immunotherapy / Infections / Macrophages - immunology / Macrophages - metabolism / Mice / Myeloid Cells - immunology / Myeloid Cells - metabolism / Neoplasms - immunology / Neoplasms - metabolism / Neoplasms - therapy / Neovascularization, Pathologic - therapy / Oncology / Oncolytic Virotherapy / Oncolytic Viruses - immunology / Original / Pediatrics / Sarcoma - immunology / Sarcoma - metabolism / Sarcoma - therapy / Simplexvirus - immunology / Stromal Cells - metabolism / Stromal Cells - virology / Surgery / Tumors / Vascular endothelial growth factor / Vascular Endothelial Growth Factor A - antagonists & inhibitors / Vascular Endothelial Growth Factor A - biosynthesis / Vascular Endothelial Growth Factor A - immunology / Virus Replication - drug effects / Xenograft Model Antitumor Assays