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Updated: Jul 30, 2025
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Vesicular Stomatitis Virus (VSV) G Glycoprotein Can Be Modified to Create a Her2/Neu-Targeted VSV That Eliminates
Yanhua Gao1, Ira Bergman1,2,3
1Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Abstract:
Viral oncolytic immunotherapy is a nascent field that is developing tools to direct the immune system to find and eliminate cancer cells. Safety is improved by using cancer-targeted viruses that infect or grow poorly on normal cells. The recent discovery of the low-density lipoprotein (LDL) receptor as the major vesicular stomatitis virus (VSV) binding site allowed for the creation of a Her2/neu-targeted replicating recombinant VSV (rrVSV-G) by eliminating the LDL receptor binding site in the VSV-G glycoprotein (gp) and adding a sequence coding for a single chain antibody (SCA) to the Her2/neu receptor. The virus was adapted by serial passage on Her2/neu-expressing cancer cells resulting in a virus that yielded a 15- to 25-fold higher titer following in vitro infection of Her2/neu+-expressing cell lines than that of Her2/neu-negative cells (~1 × 108/mL versus 4 × 106 to 8 × 106/mL). An essential mutation resulting in a higher titer virus was a threonine-to-arginine change that produced an N-glycosylation site in the SCA. Infection of Her2/neu+ subcutaneous tumors yielded >10-fold more virus on days 1 and 2 than Her2/neu- tumors, and virus production continued for 5 days in Her2/neu+ tumors compared with 3 days that of 3 days in Her2/neu- tumors. rrVSV-G cured 70% of large 5-day peritoneal tumors compared with a 10% cure by a previously targeted rrVSV with a modified Sindbis gp. rrVSV-G also cured 33% of very large 7-day tumors. rrVSV-G is a new targeted oncolytic virus that has potent antitumor capabilities and allows for heterologous combination with other targeted oncolytic viruses. IMPORTANCE A new form of vesicular stomatitis virus (VSV) was created that specifically targets and destroys cancer cells that express the Her2/neu receptor. This receptor is commonly found in human breast cancer and is associated with a poor prognosis. In laboratory tests using mouse models, the virus was highly effective at eliminating implanted tumors and creating a strong immune response against cancer. VSV has many advantages as a cancer treatment, including high levels of safety and efficacy and the ability to be combined with other oncolytic viruses to enhance treatment results or to create an effective cancer vaccine. This new virus can also be easily modified to target other cancer cell surface molecules and to add immune-modifying genes. Overall, this new VSV is a promising candidate for further development as an immune-based cancer therapy.
Insights
A novel oncolytic virus, rrVSV-G, specifically targets and eliminates Her2/neu-positive cancer cells. This engineered vesicular stomatitis virus (VSV) demonstrates potent antitumor activity in preclinical models, offering a promising new immunotherapy approach.
Area of Science:
- Oncolytic immunotherapy
- Viral vector engineering
- Cancer virology
Background:
- Oncolytic immunotherapy utilizes viruses to target and destroy cancer cells, enhancing immune responses.
- Vesicular stomatitis virus (VSV) is a candidate for oncolytic therapy due to its safety and efficacy profile.
- Targeting specific cancer cell surface receptors improves oncolytic virus specificity and reduces off-target effects.
Purpose of the Study:
- To engineer a Her2/neu-targeted replicating recombinant VSV (rrVSV-G) for enhanced cancer cell specificity.
- To evaluate the efficacy of rrVSV-G in vitro and in vivo against Her2/neu-expressing tumors.
- To assess the potential of rrVSV-G as a platform for combination cancer therapies.
Main Methods:
- Engineered VSV by modifying the VSV-G glycoprotein to eliminate LDL receptor binding and incorporate a Her2/neu-targeting single-chain antibody (SCA).
- Adapted the virus through serial passage on Her2/neu-positive cancer cells to enhance viral replication and yield.
- Assessed viral titers in vitro and viral replication in Her2/neu-positive and -negative tumors in vivo. Evaluated therapeutic efficacy in mouse models with peritoneal and subcutaneous tumors.
Main Results:
- Engineered rrVSV-G demonstrated 15- to 25-fold higher viral titers in Her2/neu-positive cell lines compared to negative controls.
- In vivo studies showed >10-fold increased viral production in Her2/neu-positive tumors, with prolonged virus shedding.
- rrVSV-G achieved significant tumor eradication, curing 70% of large peritoneal tumors and 33% of very large tumors, outperforming a previous VSV construct.
Conclusions:
- rrVSV-G is a potent, Her2/neu-targeted oncolytic virus with significant antitumor capabilities.
- The engineered virus exhibits improved tumor selectivity and replication efficiency.
- rrVSV-G represents a promising candidate for oncolytic immunotherapy and can be further developed for combination therapies or as a cancer vaccine platform.
