Targeting carcinoembryonic antigen-expressing tumors using a novel transcriptional and translational dual-regulated oncolytic herpes simplex virus type 1
VG2025 is a recombinant oncolytic herpes simplex virus type 1 (HSV-1) that uses transcriptional and translational dual regulation (TTDR) of critical viral genes to enhance virus safety and promote tumor-specific virus replication without reducing virulence. The TTDR platform is based on transcriptio...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-03-01
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| Series: | Molecular Therapy: Oncolytics |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2372770523000116 |
| _version_ | 1827994165352333312 |
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| author | Dmitry V. Chouljenko Yanal M. Murad I-Fang Lee Zahid Delwar Jun Ding Guoyu Liu Xiaohu Liu Xuexian Bu Yi Sun Ismael Samudio William Wei-Guo Jia |
| author_facet | Dmitry V. Chouljenko Yanal M. Murad I-Fang Lee Zahid Delwar Jun Ding Guoyu Liu Xiaohu Liu Xuexian Bu Yi Sun Ismael Samudio William Wei-Guo Jia |
| author_sort | Dmitry V. Chouljenko |
| collection | DOAJ |
| description | VG2025 is a recombinant oncolytic herpes simplex virus type 1 (HSV-1) that uses transcriptional and translational dual regulation (TTDR) of critical viral genes to enhance virus safety and promote tumor-specific virus replication without reducing virulence. The TTDR platform is based on transcriptional control of the essential HSV-1 immediate-early protein ICP27 using a tumor-specific carcinoembryonic antigen (CEA) promoter, coupled with translational control of the neurovirulence factor ICP34.5 using multiple microRNA (miR)-binding sites. VG2025 further incorporates IL-12 and the IL-15/IL-15 receptor alpha subunit complex to enhance the antitumor and immune stimulatory properties of oncolytic HSVs. The TTDR strategy was verified in vitro and shown to be highly selective. Strong in vivo antitumor efficacy was observed following both intratumoral and intravenous administration. Clear abscopal and immune memory effects were also evident, indicating a robust antitumor immune response. Gene expression profiling of treated tumors revealed increased immune cell infiltration and activation of multiple immune-signaling pathways when compared with the backbone virus. Absence of neurotoxicity was verified in mice and in rhesus monkeys. Taken together, the enhanced tumor clearance, excellent safety profile, and positive correlation between CEA levels and viral replication efficiency may provide an opportunity for using biomarker-based precision medicine in oncolytic virotherapy. |
| first_indexed | 2024-04-10T04:35:43Z |
| format | Article |
| id | doaj.art-e9417876f2114e71ae5406c354d90859 |
| institution | Directory Open Access Journal |
| issn | 2372-7705 |
| language | English |
| last_indexed | 2024-04-10T04:35:43Z |
| publishDate | 2023-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncolytics |
| spelling | doaj.art-e9417876f2114e71ae5406c354d908592023-03-10T04:35:23ZengElsevierMolecular Therapy: Oncolytics2372-77052023-03-0128334348Targeting carcinoembryonic antigen-expressing tumors using a novel transcriptional and translational dual-regulated oncolytic herpes simplex virus type 1Dmitry V. Chouljenko0Yanal M. Murad1I-Fang Lee2Zahid Delwar3Jun Ding4Guoyu Liu5Xiaohu Liu6Xuexian Bu7Yi Sun8Ismael Samudio9William Wei-Guo Jia10Virogin Biotech Canada Ltd., 150-13511 Commerce Parkway, Richmond, BC V6V 2J8, Canada; Corresponding author: Dmitry V. Chouljenko, Virogin Biotech Canada Ltd., 150-13511 Commerce Parkway, Richmond, BC V6V 2J8, Canada.Virogin Biotech Canada Ltd., 150-13511 Commerce Parkway, Richmond, BC V6V 2J8, CanadaVirogin Biotech Canada Ltd., 150-13511 Commerce Parkway, Richmond, BC V6V 2J8, CanadaVirogin Biotech Canada Ltd., 150-13511 Commerce Parkway, Richmond, BC V6V 2J8, CanadaVirogin Biotech Canada Ltd., 150-13511 Commerce Parkway, Richmond, BC V6V 2J8, CanadaVirogin Biotech Canada Ltd., 150-13511 Commerce Parkway, Richmond, BC V6V 2J8, CanadaVirogin Biotech Canada Ltd., 150-13511 Commerce Parkway, Richmond, BC V6V 2J8, CanadaVirogin Biotech Canada Ltd., 150-13511 Commerce Parkway, Richmond, BC V6V 2J8, CanadaVirogin Biotech Canada Ltd., 150-13511 Commerce Parkway, Richmond, BC V6V 2J8, CanadaVirogin Biotech Canada Ltd., 150-13511 Commerce Parkway, Richmond, BC V6V 2J8, CanadaVirogin Biotech Canada Ltd., 150-13511 Commerce Parkway, Richmond, BC V6V 2J8, CanadaVG2025 is a recombinant oncolytic herpes simplex virus type 1 (HSV-1) that uses transcriptional and translational dual regulation (TTDR) of critical viral genes to enhance virus safety and promote tumor-specific virus replication without reducing virulence. The TTDR platform is based on transcriptional control of the essential HSV-1 immediate-early protein ICP27 using a tumor-specific carcinoembryonic antigen (CEA) promoter, coupled with translational control of the neurovirulence factor ICP34.5 using multiple microRNA (miR)-binding sites. VG2025 further incorporates IL-12 and the IL-15/IL-15 receptor alpha subunit complex to enhance the antitumor and immune stimulatory properties of oncolytic HSVs. The TTDR strategy was verified in vitro and shown to be highly selective. Strong in vivo antitumor efficacy was observed following both intratumoral and intravenous administration. Clear abscopal and immune memory effects were also evident, indicating a robust antitumor immune response. Gene expression profiling of treated tumors revealed increased immune cell infiltration and activation of multiple immune-signaling pathways when compared with the backbone virus. Absence of neurotoxicity was verified in mice and in rhesus monkeys. Taken together, the enhanced tumor clearance, excellent safety profile, and positive correlation between CEA levels and viral replication efficiency may provide an opportunity for using biomarker-based precision medicine in oncolytic virotherapy.http://www.sciencedirect.com/science/article/pii/S2372770523000116immunotherapyoncolytic virusHSV-1cancer vaccinevirotherapymicroRNA |
| spellingShingle | Dmitry V. Chouljenko Yanal M. Murad I-Fang Lee Zahid Delwar Jun Ding Guoyu Liu Xiaohu Liu Xuexian Bu Yi Sun Ismael Samudio William Wei-Guo Jia Targeting carcinoembryonic antigen-expressing tumors using a novel transcriptional and translational dual-regulated oncolytic herpes simplex virus type 1 Molecular Therapy: Oncolytics immunotherapy oncolytic virus HSV-1 cancer vaccine virotherapy microRNA |
| title | Targeting carcinoembryonic antigen-expressing tumors using a novel transcriptional and translational dual-regulated oncolytic herpes simplex virus type 1 |
| title_full | Targeting carcinoembryonic antigen-expressing tumors using a novel transcriptional and translational dual-regulated oncolytic herpes simplex virus type 1 |
| title_fullStr | Targeting carcinoembryonic antigen-expressing tumors using a novel transcriptional and translational dual-regulated oncolytic herpes simplex virus type 1 |
| title_full_unstemmed | Targeting carcinoembryonic antigen-expressing tumors using a novel transcriptional and translational dual-regulated oncolytic herpes simplex virus type 1 |
| title_short | Targeting carcinoembryonic antigen-expressing tumors using a novel transcriptional and translational dual-regulated oncolytic herpes simplex virus type 1 |
| title_sort | targeting carcinoembryonic antigen expressing tumors using a novel transcriptional and translational dual regulated oncolytic herpes simplex virus type 1 |
| topic | immunotherapy oncolytic virus HSV-1 cancer vaccine virotherapy microRNA |
| url | http://www.sciencedirect.com/science/article/pii/S2372770523000116 |
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