High Oncolytic Activity of a Double-Deleted Vaccinia Virus Copenhagen Strain against Malignant Pleural Mesothelioma

Tiphaine Delaunay,Joelle Nader,Marion Grard,Isabelle Farine,Vera Hedwig,Johann Foloppe,Thibaut Blondy,Mathilde Violland,Daniel Pouliquen,Marc Grégoire,Nicolas Boisgerault,Philippe Erbs,Jean-François Fonteneau

doi:10.1016/j.omto.2020.08.011

Tiphaine Delaunay, Joelle Nader + Show 11 more

Open Access

https://doi.org/10.1016/j.omto.2020.08.011

Copy DOI

Abstract

Malignant pleural mesothelioma (MPM) is a cancer of the pleura that lacks efficient treatment. Oncolytic immunotherapy using oncolytic vaccinia virus (VV) may represent an alternative therapeutic approach for the treatment of this malignancy. Here, we studied the oncolytic activity of VV thymidine kinase (TK)-ribonucleotide reductase (RR)-/green fluorescent protein (GFP) against MPM. This virus is a VV from the Copenhagen strain that is deleted of two genes encoding the TK (J2R) and the RR (I4L) and that express the GFP. First, we show in vitro that VVTK-RR-/GFP efficiently infects and kills the twenty-two human MPM cell lines used in this study. We also show that the virus replicates in all eight tested MPM cell lines, however, with approximately a 10-fold difference in the amplification level from one cell line to another. Then, we studied the therapeutic efficiency of VVTK-RR-/GFP in non-obese diabetic (NOD) severe combined immunodeficient (SCID) mice that bear peritoneal human MPM tumors. One intraperitoneal infection of VVTK-RR-/GFP reduces the tumor burden and significantly increases mice survival compared to untreated animals. Thus, VVTK-RR- may be a promising oncolytic virus (OV) for the oncolytic immunotherapy of MPM.

Highlights

Malignant pleural mesothelioma (MPM) is an aggressive tumor of the pleura, usually associated with chronic asbestos exposure, mainly during occupational activities
First we assessed in vitro the oncolytic activity of the VVTK-ribonucleotide reductase (RR)-/green fluorescent protein (GFP) against 22 human MPM cell lines established from patient pleural effusion
We found that all MPM cell lines were sensitive to the infection by VVTK-RR-/GFP

Summary

Introduction

Malignant pleural mesothelioma (MPM) is an aggressive tumor of the pleura, usually associated with chronic asbestos exposure, mainly during occupational activities. Oncolytic virotherapy is a therapeutic strategy that is developing rapidly and meets recently its first success with approval of T-vec for treatment of metastatic melanoma 2. It consists in using oncolytic viruses (OV) that exclusively or preferentially replicate in tumor cells inducing their immunogenic cell death. Different oncolytic VV with inactivation of the thymidine kinase gene (TK) have been studied 4-9 These virus exerts oncolytic activities due to the high expression of TK in proliferating tumor cells that allows viral replication. This OV in combination with 5-fluorocytosine is entering in phase I/II clinical trial for the treatment of recurrent glioblastoma (clinicaltrials.gov: NCT03294486) and gastro intestinal cancer (clinicaltrials.gov: NCT03724071 and NCT04194034)

Methods

Results

Conclusion