Related Experiment Video
Updated: Jul 10, 2026
Recurrent Herpetic Stromal Keratitis in Mice, a Model for Studying Human HSK
Published on: December 18, 2012
Efficacy of Systemically Administered Retargeted Oncolytic Herpes Simplex Viruses-Clearance and Biodistribution in
Andrea Vannini1,2, Federico Parenti1, Catia Barboni3
1Department of Medical and Surgical Sciences, University of Bologna, 40126 Bologna, Italy.
Abstract:
We investigated the anticancer efficacy, blood clearance, and tissue biodistribution of systemically administered retargeted oncolytic herpes simplex viruses (ReHVs) in HSV-naïve and HSV-preimmunized (HSV-IMM) mice. Efficacy was tested against lung tumors formed upon intravenous administration of cancer cells, a model of metastatic disease, and against subcutaneous distant tumors. In naïve mice, HER2- and hPSMA-retargeted viruses, both armed with mIL-12, were highly effective, even when administered to mice with well-developed tumors. Efficacy was higher for combination regimens with immune checkpoint inhibitors. A significant amount of infectious virus persisted in the blood for at least 1 h. Viral genomes, or fragments thereof, persisted in the blood and tissues for days. Remarkably, the only sites of viral replication were the lungs of tumor-positive mice and the subcutaneous tumors. No replication was detected in other tissues, strengthening the evidence of the high cancer specificity of ReHVs, a property that renders ReHVs suitable for systemic administration. In HSV-IMM mice, ReHVs administered at late times failed to exert anticancer efficacy, and the circulating virus was rapidly inactivated. Serum stability and in vivo whole blood stability assays highlighted neutralizing antibodies as the main factor in virus inactivation. Efforts to deplete mice of the neutralizing antibodies are ongoing.
Insights
Retargeted oncolytic herpes simplex viruses (ReHVs) show potent anticancer effects in mice, replicating specifically in tumors. However, pre-existing immunity to HSV rapidly inactivates ReHVs, limiting their efficacy in previously infected individuals.
Area of Science:
- Oncolytic virotherapy
- Cancer immunotherapy
- Herpes simplex virus (HSV) engineering
Background:
- Systemic administration of oncolytic viruses is challenging due to potential off-target effects and immune inactivation.
- Retargeted oncolytic viruses (ReHVs) engineered from HSV offer potential for targeted cancer therapy.
- Pre-existing immunity to HSV can impact the efficacy of oncolytic HSV-based therapies.
Purpose of the Study:
- To evaluate the anticancer efficacy, blood clearance, and tissue biodistribution of systemically administered ReHVs.
- To assess ReHV performance in both HSV-naïve and HSV-preimmunized mouse models.
- To investigate the impact of pre-existing neutralizing antibodies on ReHV activity.
Main Methods:
- Systemic administration of HER2- and hPSMA-retargeted oncolytic herpes simplex viruses (ReHVs) armed with mIL-12.
- Efficacy testing against lung metastases and subcutaneous tumors in HSV-naïve and HSV-preimmunized mice.
- Assessment of viral blood clearance, tissue biodistribution, and replication sites.
- In vitro and in vivo stability assays to determine virus inactivation mechanisms.
Main Results:
- ReHVs demonstrated significant anticancer efficacy against lung and subcutaneous tumors in HSV-naïve mice, even in advanced disease.
- Infectious ReHVs persisted in blood for over 1 hour, with viral genomes detected in blood and tissues for days.
- Viral replication was exclusively observed in tumor sites (lungs and subcutaneous tumors), confirming high cancer specificity.
- In HSV-preimmunized mice, ReHVs showed reduced efficacy due to rapid inactivation by neutralizing antibodies.
- Serum and whole blood stability assays identified neutralizing antibodies as the primary cause of ReHV inactivation.
Conclusions:
- Systemically administered ReHVs exhibit potent, cancer-specific oncolytic activity in HSV-naïve hosts.
- Pre-existing neutralizing antibodies against HSV significantly impair ReHV efficacy, necessitating strategies to overcome this limitation.
- ReHVs hold promise for systemic cancer therapy, provided methods to circumvent pre-existing immunity are developed.
