Adenovirus with DNA Packaging Gene Mutations Increased Virus Release.

Stephen Wechman,Heshan Zhou,Kelly Mcmasters,Xiao-Mei Rao

doi:10.3390/v8120333

Abstract

Adenoviruses (Ads) have been extensively manipulated for the development of cancer selective replication, leading to cancer cell death or oncolysis. Clinical studies using E1-modified oncolytic Ads have shown that this therapeutic platform was safe, but with limited efficacy, indicating the necessity of targeting other viral genes for manipulation. To improve the therapeutic efficacy of oncolytic Ads, we treated the entire Ad genome repeatedly with UV-light and have isolated AdUV which efficiently lyses cancer cells as reported previously (Wechman, S. L. et al. Development of an Oncolytic Adenovirus with Enhanced Spread Ability through Repeated UV Irradiation and Cancer Selection. Viruses 2016, 8, 6). In this report, we show that no mutations were observed in the early genes (E1 or E4) of AdUV while several mutations were observed within the Ad late genes which have structural or viral DNA packaging functions. This study also reported the increased release of AdUV from cancer cells. In this study, we found that AdUV inhibits tumor growth following intratumoral injection. These results indicate the potentially significant role of the viral late genes, in particular the DNA packaging genes, to enhance Ad oncolysis.

Highlights

Human adenoviruses (Ads) which have been modified for cancer selective replication, known as oncolytic virotherapeutics, comprise a very promising cancer therapeutic platform for the treatment of solid tumors [1]
We have previously shown that Ad infection stimulated the activity of the cyclin E promoter [19,20], the inclusion of the cyclin E promoter to control E1a augmented the oncolytic efficacy of Ads [35,37]
We have previously developed AdUV, which was isolated from a pool of the adenovirus serotype

Summary

Introduction

Human adenoviruses (Ads) which have been modified for cancer selective replication, known as oncolytic virotherapeutics, comprise a very promising cancer therapeutic platform for the treatment of solid tumors [1]. Cancer selective Ads have very minor side effects including negligible flu-like symptoms [2]. E1b-deleted Ads, such as dl1520 and H101, have been shown to replicate within tumors while only inducing fever in a dose-dependent manner beyond those symptoms observed from cancer chemotherapy [3,4,5]. The therapeutic effects of oncolytic Ads are initiated from a small number of infected cancer cells from which progeny viruses spread to infect adjacent cancer cells within tumors [6,7]. Preclinical and clinical studies have suggested that Ad spread is restricted in large solid tumors, limiting their therapeutic efficacy [8,9,10,11,12]

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