Engineering and Characterization of Oncolytic Vaccinia Virus Expressing Truncated Herpes Simplex Virus Thymidine Kinase.

S M Bakhtiar Ul Islam,Bora Lee,Eung-Kyun Kim,Fen Jiang,Tae-Ho Hwang,Soon Cheol Ahn

doi:10.3390/cancers12010228

S M Bakhtiar Ul Islam, Bora Lee + Show 4 more

Open Access

https://doi.org/10.3390/cancers12010228

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Journal: Cancers	Publication Date: Jan 17, 2020
Citations: 13	License type: CC BY 4.0

Affiliation: Pusan National University, Sun Yat-sen University

Abstract

Oncolytic viruses are a promising class of anti-tumor agents; however, concerns regarding uncontrolled viral replication have led to the development of a replication-controllable oncolytic vaccinia virus (OVV). The engineering involves replacing the native thymidine kinase (VV-tk) gene, in a Wyeth strain vaccinia backbone, with the herpes simplex virus thymidine kinase (HSV-tk) gene, which allows for viral replication control via ganciclovir (GCV, an antiviral/cytotoxic pro-drug). Adding the wild-type HSV-tk gene might disrupt the tumor selectivity of VV-tk deleted OVVs; therefore, only engineered viruses that lacked tk activity were selected as candidates. Ultimately, OTS-412, which is an OVV containing a mutant HSV-tk, was chosen for characterization regarding tumor selectivity, sensitivity to GCV, and the influence of GCV on OTS-412 anti-tumor effects. OTS-412 demonstrated comparable replication and cytotoxicity to VVtk- (control, a VV-tk deleted OVV) in multiple cancer cell lines. In HCT 116 mouse models, OTS-412 replication in tumors was reduced by >50% by GCV (p = 0.004); additionally, combination use of GCV did not compromise the anti-tumor effects of OTS-412. This is the first report of OTS-412, a VV-tk deleted OVV containing a mutant HSV-tk transgene, which demonstrates tumor selectivity and sensitivity to GCV. The HSV-tk/GCV combination provides a safety mechanism for future clinical applications of OTS-412.

Highlights

Scientists discovered that viruses can kill cancer cells over a century ago, interest in oncolytic virus research has been slow to develop until recently [1]
Vaccinia virus (VACV) is one of the more preferred backbones for oncolytic virus engineering based on its long history of use as the routine vaccine for smallpox [8]
Current clinical data suggest that the efficacy of oncolytic vaccinia virus (OVV) treatment tends to be dose-dependent [9]

Summary

Introduction

Scientists discovered that viruses can kill cancer cells over a century ago, interest in oncolytic virus research has been slow to develop until recently [1]. Administration (FDA) and European Medicines Agency (EMA) approved their first oncolytic virus, T-VEC, a genetically engineered herpes simplex virus, for the treatment of advanced melanoma [2]. Vaccinia virus (VACV) is one of the more preferred backbones for oncolytic virus engineering based on its long history of use as the routine vaccine for smallpox [8]. Current clinical data suggest that the efficacy of oncolytic vaccinia virus (OVV) treatment tends to be dose-dependent [9]. High-level, persistent viral replication can be cause for major safety concerns when dealing with replication-competent oncolytic viruses, including OVV, as addressed by the US FDA in the guidance of Preclinical Assessment of Investigational Cellular and Gene Therapy Products (November 2013)

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