Deletion of Apoptosis Inhibitor F1L in Vaccinia Virus Increases Safety and Oncolysis for Cancer Therapy
| Autor: | Elena Scut, Madison Foster, Philippe Erbs, Adrian Pelin, Johann Foloppe, Victoria A. Jennings, Marian Hussein, Lawton J. Stubbert, Brian Laight, Antonio Postigo, Michael Way, Fabrice Le Boeuf, Florian Gossart, Julia Petryk, Christopher J Storbeck, Ragunath Singaravelu, John C. Bell |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Programmed cell death viruses Biology lcsh:RC254-282 Virus Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Pharmacology (medical) Smallpox vaccine Cancer medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Virology 3. Good health Oncolytic virus 030104 developmental biology Oncology chemistry Thymidine kinase 030220 oncology & carcinogenesis Cancer cell Molecular Medicine Vaccinia |
| Zdroj: | Molecular Therapy: Oncolytics, Vol 14, Iss, Pp 246-252 (2019) Molecular Therapy Oncolytics |
| ISSN: | 2372-7705 |
| Popis: | Vaccinia virus (VACV) possesses a great safety record as a smallpox vaccine and has been intensively used as an oncolytic virus against various types of cancer over the past decade. Different strategies were developed to make VACV safe and selective to cancer cells. Leading clinical candidates, such as Pexa-Vec, are attenuated through deletion of the viral thymidine kinase (TK) gene, which limits virus growth to replicate in cancer tissue. However, tumors are not the only tissues whose metabolic activity can overcome the lack of viral TK. In this study, we sought to further increase the tumor-specific replication and oncolytic potential of Copenhagen strain VACV ΔTK. We show that deletion of the anti-apoptosis viral gene F1L not only increases the safety of the Copenhagen ΔTK virus but also improves its oncolytic activity in an aggressive glioblastoma model. The additional loss of F1L does not affect VACV replication capacity, yet its ability to induce cancer cell death is significantly increased. Our results also indicate that cell death induced by the Copenhagen ΔTK/F1L mutant releases more immunogenic signals, as indicated by increased levels of IL-1β production. A cytotoxicity screen in an NCI-60 panel shows that the ΔTK/F1L virus induces faster tumor cell death in different cancer types. Most importantly, we show that, compared to the TK-deleted virus, the ΔTK/F1L virus is attenuated in human normal cells and causes fewer pox lesions in murine models. Collectively, our findings describe a new oncolytic vaccinia deletion strain that improves safety and increases tumor cell killing. |
| Databáze: | OpenAIRE |
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