1. VEGF Blockade Enables Oncolytic Cancer Virotherapy in Part by Modulating Intratumoral Myeloid Cells
- Author
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David A. Hildeman, Francis Eshun, Keri A. Streby, Margaret H. Collins, Timothy P. Cripe, Louis Boon, William F. Goins, Jason S. Frischer, Amy Haseley, Allyson Sholl, Pin Yi Wang, Senad Divanovic, Brett W. Hendrickson, Mark A. Currier, Artur Chernoguz, Balveen Kaur, Jennifer L. Leddon, Rolf A. Brekken, Kelly M. Crawford, and William H. Baird
- Subjects
Vascular Endothelial Growth Factor A ,Myeloid ,Angiogenesis ,Cell Culture Techniques ,Virus Replication ,medicine.disease_cause ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Neoplasms ,Drug Discovery ,Simplexvirus ,Myeloid Cells ,Cytotoxicity ,Oncolytic Virotherapy ,0303 health sciences ,CD11b Antigen ,Neovascularization, Pathologic ,Sarcoma ,3. Good health ,Bevacizumab ,Vascular endothelial growth factor ,Oncolytic Viruses ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Molecular Medicine ,Female ,Original Article ,Genetic Vectors ,Biology ,Antibodies, Monoclonal, Humanized ,Virus ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Genetics ,Animals ,Humans ,Virotherapy ,Molecular Biology ,030304 developmental biology ,Pharmacology ,Macrophages ,Xenograft Model Antitumor Assays ,Oncolytic virus ,Disease Models, Animal ,Herpes simplex virus ,chemistry ,Immunology ,Cancer research ,Stromal 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.
- Published
- 2013
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