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Updated: Jun 29, 2025
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Oncolytic varicella-zoster virus engineered with ORF8 deletion and armed with drug-controllable interleukin-12
Haifei Jiang1, Rebecca Nace2, Talia Fernandez Carrasco2
1Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA Jiang.Haifei@mayo.edu sjrussell@vyriad.com.
Background:
The varicella-zoster virus (VZV), belonging to the group of human α-herpesviruses, has yet to be developed as a platform for oncolytic virotherapy, despite indications from clinical case reports suggesting a potential association between VZV infection and cancer remission.
Methods:
Here, we constructed oncolytic VZV candidates based on the vaccine strain vOka and the laboratory strain Ellen. These newly engineered viruses were subsequently assessed for their oncolytic properties in the human MeWo melanoma xenograft model and the mouse B16-F10-nectin1 melanoma syngeneic model.
Results:
In the MeWo xenograft model, both vOka and Ellen exhibited potent antitumor efficacy. However, it was observed that introducing a hyperfusogenic mutation into glycoprotein B led to a reduction in VZV's effectiveness. Notably, the deletion of ORF8 (encodes viral deoxyuridine triphosphatase) attenuated the replication of VZV both in vitro and in vivo, but it did not compromise VZV's oncolytic potency. We further armed the VZV Ellen-ΔORF8 vector with a tet-off controlled mouse single-chain IL12 (scIL12) gene cassette. This augmented virus was validated for its oncolytic activity and triggered systemic antitumor immune responses in the immunocompetent B16-F10-nectin1 model.
Conclusions:
These findings highlight the potential of using Ellen-ΔORF8-tet-off-scIL12 as a novel VZV-based oncolytic virotherapy.
Insights
Oncolytic varicella-zoster virus (VZV) shows promise for cancer therapy. Engineered VZV strains demonstrated potent antitumor effects, with a modified Ellen-ΔORF8 strain armed with IL12 showing significant potential for virotherapy.
Area of Science:
- Virology
- Oncology
- Gene Therapy
Background:
- Varicella-zoster virus (VZV), a human alpha-herpesvirus, has potential for oncolytic virotherapy.
- Clinical reports suggest a link between VZV infection and cancer remission.
Purpose of the Study:
- To engineer and evaluate VZV-based oncolytic virus candidates.
- To assess their efficacy in preclinical cancer models.
Main Methods:
- Constructed oncolytic VZV candidates using vaccine (vOka) and laboratory (Ellen) strains.
- Evaluated oncolytic properties in MeWo melanoma xenografts and B16-F10-nectin1 melanoma syngeneic models.
- Modified VZV by deleting ORF8 and introducing a hyperfusogenic mutation; armed with IL12 gene cassette.
Main Results:
- Both vOka and Ellen showed antitumor efficacy in xenografts.
- Hyperfusogenic mutation reduced VZV effectiveness.
- ORF8 deletion attenuated VZV replication but maintained oncolytic potency.
- Armed Ellen-ΔORF8-tet-off-scIL12 triggered systemic antitumor immune responses.
Conclusions:
- Ellen-ΔORF8-tet-off-scIL12 is a promising VZV-based oncolytic virotherapy candidate.
- VZV engineering can enhance oncolytic and immunotherapeutic properties.
