Triple‐mutated oncolytic herpes virus for treating both fast‐ and slow‐growing tumors

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.