Novel Oncolytic Virus Armed with Cancer Suicide Gene and Normal Vasculogenic Gene for Improved Anti-Tumor Activity.

Su-Nam Jeong,So Young Yoo

doi:10.3390/cancers12051070

Abstract

Here, we developed a novel oncolytic vaccinia virus (NOV) with the dual advantages of cancer selectivity and normal vessel reconstructive activity by replacing the viral thymidine kinase (vTk) and vaccinia growth factor (VGF) genes with genes encoding TNF-related apoptosis-inducing ligand (TRAIL) and angiopoietin 1 (Ang1), respectively. The pan-cancer-specific oncolytic potency of NOV was confirmed in various human and mouse cancer cell lines (colon, liver, pancreas, cholangiocarcinoma, cervical cancer, osteosarcoma, and melanoma). Vaccinia virus (VV) treatment directly induced early apoptosis in tumors within 24 h, and this effect was enhanced with further engineering; VGF and Tk deletion with Ang1 and TRAIL insertion. Meanwhile, treatment with the conventional anti-cancer drug cisplatin did not induce apoptosis. A virus-treated CT26 mouse colon cancer syngeneic model showed attenuated tumor growth, which was in accordance with the results of percent survival measurement, CD8 expression analysis, and TUNEL staining with advanced genetic engineering (vAng1 < vTRAIL < NOV). Taken together, our results indicate that NOV induces cancer tissue apoptosis and anti-tumor immunity and may constitute a highly advantageous therapeutic agent for next-generation solid tumor virotherapy with pan-cancer-specific oncolytic activity and high biosafety.

Highlights

Oncolytic viruses (OVs) are currently used for cancer treatment, especially in cases of advanced cancers that are refractory to conventional therapies such as chemotherapy and radiotherapy
angiopoietin 1 (Ang1), which is involved in normal vessel formation, to improve drug delivery and normal tissue reconstruction during the oncolytic process
We developed novel oncolytic vaccinia virus (NOV), which exhibits the dual advantages of cancer selectivity and normal vessel reconstructive properties as a result of the expression of Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and Ang1 in the place of viral thymidine kinase (vTk) and vaccinia growth factor (VGF), respectively (Figure 1)

Summary

Introduction

Oncolytic viruses (OVs) are currently used for cancer treatment, especially in cases of advanced cancers that are refractory to conventional therapies such as chemotherapy and radiotherapy. Oncolytic virotherapy (OVT), which is an effective technique that is distinct from other general gene therapies, utilizes OVs as molecular cancer therapeutic agents [1,2,3,4,5]. OVs are utilized excellently for this purpose; they are stable and clinically available because they selectively infect and replicate in cancer cells. Since Amgen’s FDA (Food and Drug Administration) approval of talimogene laherparepvec (T-VEC), clinical trials at SillaJen with pexastimogene devacirepvec (Pexa-Vec), a recombinant vaccinia virus, and other recombinant OVs have been initiated and are currently ongoing [2,9,10]

Methods

Results

Discussion

Conclusion