Eliciting an immune-mediated antitumor response through oncolytic herpes simplex virus-based shared antigen expression in tumors resistant to viroimmunotherapy
Background Oncolytic virotherapy (OV) is an immunotherapy that incorporates viral cancer cell lysis with engagement of the recruited immune response against cancer cells. Pediatric solid tumors are challenging targets because they contain both an inert immune environment and a quiet antigenic landsc...
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BMJ Publishing Group
2021-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/9/10/e002939.full |
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| author | Chun-Yu Chen Mohammed G Ghonime Uksha Saini Michael C Kelly Justin C Roth Pin-Yi Wang Katherine Miller Ilse Hernandez-Aguirre Yeaseul Kim Xiaokui Mo Joseph R Stanek Tim Cripe Elaine Mardis Kevin A Cassady |
| author_facet | Chun-Yu Chen Mohammed G Ghonime Uksha Saini Michael C Kelly Justin C Roth Pin-Yi Wang Katherine Miller Ilse Hernandez-Aguirre Yeaseul Kim Xiaokui Mo Joseph R Stanek Tim Cripe Elaine Mardis Kevin A Cassady |
| author_sort | Chun-Yu Chen |
| collection | DOAJ |
| description | Background Oncolytic virotherapy (OV) is an immunotherapy that incorporates viral cancer cell lysis with engagement of the recruited immune response against cancer cells. Pediatric solid tumors are challenging targets because they contain both an inert immune environment and a quiet antigenic landscape, making them more resistant to conventional OV approaches. Further complicating this, herpes simplex virus suppresses host gene expression during virotherapy infection.Methods We therefore developed a multimodal oncolytic herpes simplex virus (oHSV) that expresses ephrin A2 (EphA2), a shared tumor-associated antigen (TAA) expressed by many tumors to improve immune-mediated antitumor activity. We verified the virus genotypically and phenotypically and then tested it in an oHSV-resistant orthotopic model (including immunophenotypic analysis), in flank and in T cell-deficient mouse models. We then assessed the antigen-expressing virus in an unrelated peripheral tumor model that also expresses the shared tumor antigen and evaluated functional T-cell response from the treated mice.Results Virus-based EphA2 expression induces a robust acquired antitumor immune responses in both an oHSV-resistant murine brain and peripheral tumor model. Our new multimodal oncolytic virus (1) improves survival in viroimmunotherapy resistant tumors, (2) alters both the infiltrating and peripheral T-cell populations capable of suppressing tumor growth on rechallenge, and (3) produces EphA2-specific CD8 effector-like populations.Conclusions Our results suggest that this flexible viral-based platform enables immune recognition of the shared TAA and improves the immune-therapeutic response, thus making it well suited for low-mutational load tumors. |
| format | Article |
| id | doaj-art-000e2ddeb46142639945f4ab424b5abd |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2021-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-000e2ddeb46142639945f4ab424b5abd2025-08-20T01:53:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262021-10-0191010.1136/jitc-2021-002939Eliciting an immune-mediated antitumor response through oncolytic herpes simplex virus-based shared antigen expression in tumors resistant to viroimmunotherapyChun-Yu Chen0Mohammed G Ghonime1Uksha Saini2Michael C Kelly3Justin C Roth4Pin-Yi Wang5Katherine Miller6Ilse Hernandez-Aguirre7Yeaseul Kim8Xiaokui Mo9Joseph R Stanek10Tim Cripe11Elaine Mardis12Kevin A Cassady13Center for Childhood Cancer and Blood Disorders, Abigail Wexner Research Institute at Nationwide Children`s Hospital, Columbus, Ohio, USACenter for Childhood Cancer and Blood Disorders, Abigail Wexner Research Institute at Nationwide Children`s Hospital, Columbus, Ohio, USA1Nationwide Children’s Hospital, Columbus, OH, USACenter for Childhood Cancer and Blood Disorders, Abigail Wexner Research Institute at Nationwide Children`s Hospital, Columbus, Ohio, USAThe University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USACenter for Childhood Cancer and Blood Disorders, Abigail Wexner Research Institute at Nationwide Children`s Hospital, Columbus, Ohio, USA1Nationwide Children’s Hospital, Columbus, OH, USACollege of Medicine, The Ohio State University, Columbus, Ohio, USA1Nationwide Children’s Hospital, Columbus, OH, USABiostatistics, The Ohio State University, Columbus, Ohio, USABiostatistics Resource, Nationwide Children`s Hospital, Columbus, Ohio, USACenter for Childhood Cancer and Blood Disorders, Abigail Wexner Research Institute at Nationwide Children`s Hospital, Columbus, Ohio, USA1Nationwide Children’s Hospital, Columbus, OH, USA1Nationwide Children’s Hospital, Columbus, OH, USABackground Oncolytic virotherapy (OV) is an immunotherapy that incorporates viral cancer cell lysis with engagement of the recruited immune response against cancer cells. Pediatric solid tumors are challenging targets because they contain both an inert immune environment and a quiet antigenic landscape, making them more resistant to conventional OV approaches. Further complicating this, herpes simplex virus suppresses host gene expression during virotherapy infection.Methods We therefore developed a multimodal oncolytic herpes simplex virus (oHSV) that expresses ephrin A2 (EphA2), a shared tumor-associated antigen (TAA) expressed by many tumors to improve immune-mediated antitumor activity. We verified the virus genotypically and phenotypically and then tested it in an oHSV-resistant orthotopic model (including immunophenotypic analysis), in flank and in T cell-deficient mouse models. We then assessed the antigen-expressing virus in an unrelated peripheral tumor model that also expresses the shared tumor antigen and evaluated functional T-cell response from the treated mice.Results Virus-based EphA2 expression induces a robust acquired antitumor immune responses in both an oHSV-resistant murine brain and peripheral tumor model. Our new multimodal oncolytic virus (1) improves survival in viroimmunotherapy resistant tumors, (2) alters both the infiltrating and peripheral T-cell populations capable of suppressing tumor growth on rechallenge, and (3) produces EphA2-specific CD8 effector-like populations.Conclusions Our results suggest that this flexible viral-based platform enables immune recognition of the shared TAA and improves the immune-therapeutic response, thus making it well suited for low-mutational load tumors.https://jitc.bmj.com/content/9/10/e002939.full |
| spellingShingle | Chun-Yu Chen Mohammed G Ghonime Uksha Saini Michael C Kelly Justin C Roth Pin-Yi Wang Katherine Miller Ilse Hernandez-Aguirre Yeaseul Kim Xiaokui Mo Joseph R Stanek Tim Cripe Elaine Mardis Kevin A Cassady Eliciting an immune-mediated antitumor response through oncolytic herpes simplex virus-based shared antigen expression in tumors resistant to viroimmunotherapy Journal for ImmunoTherapy of Cancer |
| title | Eliciting an immune-mediated antitumor response through oncolytic herpes simplex virus-based shared antigen expression in tumors resistant to viroimmunotherapy |
| title_full | Eliciting an immune-mediated antitumor response through oncolytic herpes simplex virus-based shared antigen expression in tumors resistant to viroimmunotherapy |
| title_fullStr | Eliciting an immune-mediated antitumor response through oncolytic herpes simplex virus-based shared antigen expression in tumors resistant to viroimmunotherapy |
| title_full_unstemmed | Eliciting an immune-mediated antitumor response through oncolytic herpes simplex virus-based shared antigen expression in tumors resistant to viroimmunotherapy |
| title_short | Eliciting an immune-mediated antitumor response through oncolytic herpes simplex virus-based shared antigen expression in tumors resistant to viroimmunotherapy |
| title_sort | eliciting an immune mediated antitumor response through oncolytic herpes simplex virus based shared antigen expression in tumors resistant to viroimmunotherapy |
| url | https://jitc.bmj.com/content/9/10/e002939.full |
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