Retargeting Strategies for Oncolytic Herpes Simplex Viruses

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.