VEGF Blockade Enables Oncolytic Cancer Virotherapy in Part by Modulating Intratumoral Myeloid Cells
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 antitumo...
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| Veröffentlicht in: | Molecular therapy 2013-05, Vol.21 (5), p.1014-1023 |
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| creator | Currier, Mark A Eshun, Francis K Sholl, Allyson Chernoguz, Artur Crawford, Kelly Divanovic, Senad Boon, Louis Goins, William F Frischer, Jason S Collins, Margaret H Leddon, Jennifer L Baird, William H Haseley, Amy Streby, Keri A Wang, Pin-Yi Hendrickson, Brett W Brekken, Rolf A Kaur, Balveen Hildeman, David Cripe, Timothy P |
| description | 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. |
| doi_str_mv | 10.1038/mt.2013.39 |
| format | Article |
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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.</description><identifier>ISSN: 1525-0016</identifier><identifier>EISSN: 1525-0024</identifier><identifier>DOI: 10.1038/mt.2013.39</identifier><identifier>PMID: 23481323</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><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</subject><ispartof>Molecular therapy, 2013-05, Vol.21 (5), p.1014-1023</ispartof><rights>2013 The American Society of Gene & Cell Therapy</rights><rights>Copyright Nature Publishing Group May 2013</rights><rights>Copyright © 2013 The American Society of Gene & Cell Therapy 2013 The American Society of Gene & Cell Therapy</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c484t-aaf2efe6bdc60d3207ec71d8185982542e2a0eb6ffcd189b448d0c2054a59cbc3</citedby><cites>FETCH-LOGICAL-c484t-aaf2efe6bdc60d3207ec71d8185982542e2a0eb6ffcd189b448d0c2054a59cbc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3666636/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3666636/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23481323$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Currier, Mark A</creatorcontrib><creatorcontrib>Eshun, Francis K</creatorcontrib><creatorcontrib>Sholl, Allyson</creatorcontrib><creatorcontrib>Chernoguz, Artur</creatorcontrib><creatorcontrib>Crawford, Kelly</creatorcontrib><creatorcontrib>Divanovic, Senad</creatorcontrib><creatorcontrib>Boon, Louis</creatorcontrib><creatorcontrib>Goins, William F</creatorcontrib><creatorcontrib>Frischer, Jason S</creatorcontrib><creatorcontrib>Collins, Margaret H</creatorcontrib><creatorcontrib>Leddon, Jennifer L</creatorcontrib><creatorcontrib>Baird, William H</creatorcontrib><creatorcontrib>Haseley, Amy</creatorcontrib><creatorcontrib>Streby, Keri A</creatorcontrib><creatorcontrib>Wang, Pin-Yi</creatorcontrib><creatorcontrib>Hendrickson, Brett W</creatorcontrib><creatorcontrib>Brekken, Rolf A</creatorcontrib><creatorcontrib>Kaur, Balveen</creatorcontrib><creatorcontrib>Hildeman, David</creatorcontrib><creatorcontrib>Cripe, Timothy P</creatorcontrib><title>VEGF Blockade Enables Oncolytic Cancer Virotherapy in Part by Modulating Intratumoral Myeloid Cells</title><title>Molecular therapy</title><addtitle>Mol Ther</addtitle><description>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.</description><subject>Angiogenesis</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antibodies, Monoclonal, Humanized - administration & dosage</subject><subject>Antibodies, Monoclonal, Humanized - pharmacology</subject><subject>Bevacizumab</subject><subject>Cancer</subject><subject>CD11b Antigen - metabolism</subject><subject>Cell Culture Techniques</subject><subject>Cell Line, Tumor</subject><subject>Cells</subject><subject>Cytokines</subject><subject>Cytotoxicity</subject><subject>Disease</subject><subject>Disease Models, Animal</subject><subject>Ewings sarcoma</subject><subject>Female</subject><subject>Genetic Vectors - administration & dosage</subject><subject>Genetic Vectors - immunology</subject><subject>Hematology</subject><subject>Herpes simplex virus</subject><subject>Herpes viruses</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Immunotherapy</subject><subject>Infections</subject><subject>Macrophages - immunology</subject><subject>Macrophages - metabolism</subject><subject>Mice</subject><subject>Myeloid Cells - immunology</subject><subject>Myeloid Cells - metabolism</subject><subject>Neoplasms - immunology</subject><subject>Neoplasms - metabolism</subject><subject>Neoplasms - therapy</subject><subject>Neovascularization, Pathologic - therapy</subject><subject>Oncology</subject><subject>Oncolytic Virotherapy</subject><subject>Oncolytic Viruses - immunology</subject><subject>Original</subject><subject>Pediatrics</subject><subject>Sarcoma - immunology</subject><subject>Sarcoma - metabolism</subject><subject>Sarcoma - therapy</subject><subject>Simplexvirus - immunology</subject><subject>Stromal Cells - metabolism</subject><subject>Stromal Cells - virology</subject><subject>Surgery</subject><subject>Tumors</subject><subject>Vascular endothelial growth factor</subject><subject>Vascular Endothelial Growth Factor A - antagonists & inhibitors</subject><subject>Vascular Endothelial Growth Factor A - 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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.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>23481323</pmid><doi>10.1038/mt.2013.39</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | Molecular therapy, 2013-05, Vol.21 (5), p.1014-1023 |
| issn | 1525-0016 1525-0024 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3666636 |
| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection |
| subjects | 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 |
| title | VEGF Blockade Enables Oncolytic Cancer Virotherapy in Part by Modulating Intratumoral Myeloid Cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-27T13%3A30%3A09IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=VEGF%20Blockade%20Enables%20Oncolytic%20Cancer%20Virotherapy%20in%20Part%20by%20Modulating%20Intratumoral%20Myeloid%20Cells&rft.jtitle=Molecular%20therapy&rft.au=Currier,%20Mark%20A&rft.date=2013-05-01&rft.volume=21&rft.issue=5&rft.spage=1014&rft.epage=1023&rft.pages=1014-1023&rft.issn=1525-0016&rft.eissn=1525-0024&rft_id=info:doi/10.1038/mt.2013.39&rft_dat=%3Cproquest_pubme%3E1668244967%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1792507560&rft_id=info:pmid/23481323&rft_els_id=S1525001616306815&rfr_iscdi=true |