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Updated: Mar 24, 2026
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Retargeting Strategies for Oncolytic Herpes Simplex Viruses
Gabriella Campadelli-Fiume1, Biljana Petrovic2, Valerio Leoni3
1Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna 40126, Italy. gabriella.campadelli@unibo.it.
Abstract:
Most of the oncolytic herpes simplex viruses (HSVs) exhibit a high safety profile achieved through attenuation. They carry defects in virulence proteins that antagonize host cell response to the virus, including innate response, apoptosis, authophagy, and depend on tumor cell proliferation. They grow robustly in cancer cells, provided that these are deficient in host cell responses, which is often the case. To overcome the attenuation limits, a strategy is to render the virus highly cancer-specific, e.g., by retargeting their tropism to cancer-specific receptors, and detargeting from natural receptors. The target we selected is HER-2, overexpressed in breast, ovarian and other cancers. Entry of wt-HSV requires the essential glycoproteins gD, gH/gL and gB. Here, we reviewed that oncolytic HSV retargeting was achieved through modifications in gD: the addition of a single-chain antibody (scFv) to HER-2 coupled with appropriate deletions to remove part of the natural receptors' binding sites. Recently, we showed that also gH/gL can be a retargeting tool. The insertion of an scFv to HER-2 at the gH N-terminus, coupled with deletions in gD, led to a recombinant capable to use HER-2 as the sole receptor. The retargeted oncolytic HSVs can be administered systemically by means of carrier cells-forcedly-infected mesenchymal stem cells. Altogether, the retargeted oncolytic HSVs are highly cancer-specific and their replication is not dependent on intrinsic defects of the tumor cells. They might be further modified to express immunomodulatory molecules.
Insights
Engineered oncolytic herpes simplex viruses (HSVs) target HER-2 for enhanced cancer specificity. These modified HSVs overcome limitations of traditional attenuated viruses, offering a promising cancer therapy approach.
Area of Science:
- Oncolytic virotherapy
- Molecular virology
- Cancer biology
Background:
- Attenuated oncolytic herpes simplex viruses (HSVs) have a good safety profile but depend on tumor cell defects for replication.
- Overcoming attenuation limits requires enhancing cancer specificity through receptor retargeting.
- HER-2 is a key target due to its overexpression in various cancers like breast and ovarian.
Purpose of the Study:
- To review strategies for retargeting oncolytic HSV to cancer-specific receptors, focusing on HER-2.
- To explore modifications in HSV glycoproteins (gD and gH/gL) for HER-2 targeting.
- To discuss the potential of systemically administered, retargeted oncolytic HSVs.
Main Methods:
- Modifications of HSV glycoprotein D (gD) by adding a HER-2 specific single-chain antibody (scFv) and deleting natural receptor binding sites.
- Utilizing HSV glycoprotein H/L (gH/gL) as a retargeting tool by inserting an scFv to HER-2.
- Engineering recombinant HSVs to use HER-2 as the sole entry receptor.
Main Results:
- Retargeting of oncolytic HSV to HER-2 was achieved through modifications in gD or gH/gL.
- A recombinant HSV was developed using HER-2 as the sole receptor via gH/gL modification and gD deletions.
- Retargeted HSVs demonstrated high cancer specificity, independent of intrinsic tumor cell defects.
Conclusions:
- Retargeted oncolytic HSVs offer improved cancer specificity by utilizing cancer-specific receptors like HER-2.
- Systemic delivery of retargeted HSVs is feasible using carrier cells, such as mesenchymal stem cells.
- Further modifications for expressing immunomodulatory molecules could enhance the therapeutic potential of these oncolytic viruses.
