VEGF Blockade Enables Oncolytic Cancer Virotherapy in Part by Modulating Intratumoral Myeloid Cells
| Autor: | 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, William H. Baird |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
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 |
| Zdroj: | Molecular Therapy. 21(5):1014-1023 |
| ISSN: | 1525-0016 |
| DOI: | 10.1038/mt.2013.39 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|