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Updated: Nov 4, 2025
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Triple-mutated oncolytic herpes virus for treating both fast- and slow-growing tumors
Hiroshi Fukuhara1,2, Yuta Takeshima2, Tomoki Todo2
1Department of Urology, Kyorin University School of Medicine, Tokyo, Japan.
Abstract:
Oncolytic virus therapy has emerged as a promising treatment option against cancer. To date, oncolytic viruses have been developed for malignant tumors, but the need for this new therapeutic modality also exists for benign and slow-growing tumors. G47∆ is an oncolytic herpes simplex virus type 1 (HSV-1) with an enhanced replication capability highly selective to tumor cells due to genetically engineered, triple mutations in the γ34.5, ICP6 and α47 genes. To create a powerful, but safe oncolytic HSV-1 that replicates efficiently in tumors regardless of growth speed, we used a bacterial artificial chromosome system that allows a desired promoter to regulate the expression of the ICP6 gene in the G47∆ backbone. Restoration of the ICP6 function in a tumor-specific manner using the hTERT promoter led to a highly capable oncolytic HSV-1. T-hTERT was more efficacious in the slow-growing OS-RC-2 and DU145 tumors than the control viruses, while retaining a high efficacy in the fast-growing U87MG tumors. The safety features are also retained, as T-hTERT proved safe when inoculated into the brain of HSV-1 sensitive A/J mice. This new technology should facilitate the use of oncolytic HSV-1 for all tumors irrespective of growth speed.
Insights
A novel oncolytic herpes simplex virus type 1 (HSV-1), T-hTERT, demonstrates potent efficacy against slow-growing tumors. This enhanced oncolytic virus therapy shows promise for treating a wider range of tumors, including benign and malignant types.
Area of Science:
- Oncolytic virotherapy
- Cancer therapeutics
- Viral oncology
Background:
- Oncolytic virus therapy is a promising cancer treatment.
- Existing oncolytic viruses are mainly developed for malignant tumors.
- Benign and slow-growing tumors also require effective oncolytic virus treatments.
Purpose of the Study:
- To engineer a safe and effective oncolytic herpes simplex virus type 1 (HSV-1) capable of efficient tumor replication, irrespective of tumor growth speed.
- To enhance the efficacy of oncolytic HSV-1 for slow-growing tumors.
Main Methods:
- Genetically engineered G47∆ oncolytic HSV-1 using a bacterial artificial chromosome system.
- Regulated ICP6 gene expression via the hTERT promoter for tumor-specific replication.
- Evaluated T-hTERT efficacy in fast-growing (U87MG) and slow-growing (OS-RC-2, DU145) tumor models.
- Assessed safety by inoculating T-hTERT into the brain of A/J mice.
Main Results:
- T-hTERT demonstrated superior efficacy in slow-growing OS-RC-2 and DU145 tumors compared to control viruses.
- High efficacy was maintained in fast-growing U87MG tumors.
- T-hTERT exhibited a favorable safety profile in mice, even when administered intracranially.
Conclusions:
- Tumor-specific restoration of ICP6 function using the hTERT promoter creates a potent oncolytic HSV-1.
- T-hTERT shows enhanced efficacy against slow-growing tumors while retaining effectiveness against fast-growing ones.
- This technology broadens the applicability of oncolytic HSV-1 therapy to diverse tumor types.
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