Oncolytic efficacy of thymidine kinase-deleted vaccinia virus strain Guang9.

Lili Deng,Yuedi Ding,Bin Zhou,Biao Huang,Jun Fan,Jue Zhang,Yi Zhang

doi:10.18632/oncotarget.17125

Abstract

Oncolytic virotherapy is being developed as a promising platform for cancer therapy due to its ability to lyse cancer cells in a tumor-specific manner. Vaccinia virus has been used as a live vaccine in the smallpox eradication program and now is being potential in cancer therapy with a great safety profile. Vaccinia strain Guang9 (VG9) is an attenuated Chinese vaccinia virus and its oncolytic efficacy has been evaluated in our previous study. To improve the tumor selectivity and oncolytic efficacy, we here developed a thymidine kinase (TK)-deleted vaccinia virus based on Guang9 strain. The viral replication, marker gene expression and cytotoxicity in various cell lines were evaluated; antitumor effects in vivo were assessed in multiple tumor models. In vitro, the TK-deleted vaccinia virus replicated rapidly, but the cytotoxicity varied in different cell lines. It was notably attenuated in normal cells and resting cells in vitro, while tumor-selectively replicated in vivo. Significant antitumor effects were observed both in murine melanoma tumor model and human hepatoma tumor model. It significantly inhibited the growth of subcutaneously implanted tumors and prolonged the survival of tumor-bearing mice. Collectively, TK-deleted vaccinia strain Guang9 is a promising constructive virus vector for tumor-directed gene therapy and will be a potential therapeutic strategy in cancer treatment.

Highlights

Oncolytic virotherapy has recently been emerged as a promising and appealing strategy for combating cancer [1,2,3,4,5]
The thymidine kinase (TK)-deleted recombinant vaccinia virus expressing enhanced green fluorescent protein (EGFP) gene was generated from the attenuated Chinese vaccinia strain Vaccinia strain Guang9 (VG9)
A shuttle plasmid was used to insert EGFP into TK locus by homologous recombination, creating TK-deleted vaccinia virus, VG9EGFP (Figure 1A)

Summary

Introduction

Oncolytic virotherapy has recently been emerged as a promising and appealing strategy for combating cancer [1,2,3,4,5]. A variety of viruses are under investigation for treatment of cancer, including adenovirus, herpes virus, Newcastle disease virus, and vaccinia virus [6,7,8,9]. Vaccinia virus has some excellent characteristics over other viruses, such as large transgene-encoding capacity, efficient foreign gene expression using its own enzyme systems, and selective replication in tumor tissues. Vaccinia virus has been used as a live vaccine in the smallpox eradication campaign and recently as a vaccine against other infectious diseases and cancer [10, 11]. Due to the safety as a systemically administered replicating virus, it has not been extended applied as the tumor-directed gene therapy vector [12, 13]. Various modifications toward improving tumor specificity and safety have been explored [18,19,20]

Methods

Results

Conclusion