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

Our plain-English summary of High Oncolytic Activity of a Double-Deleted Vaccinia Virus Copenhagen Strain against Malignant Pleural Mesothelioma, by T. Delaunay, J. Nader, M. Grard, et al (Molecular Therapy Oncolytics, 2020).

The study

• Authors: T. Delaunay, J. Nader, M. Grard, I. Farine, V. Hedwig, J. Foloppe, T. Blondy, M. Violland, D. Pouliquen, M. Grégoire, N. Boisgerault, P. Erbs, J.F. Fonteneau
• Journal: Molecular Therapy Oncolytics
• Published: 2020;18:573-578
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2020 The Authors.

In plain English

This laboratory study tested an oncolytic vaccinia virus of the Copenhagen strain, deleted of the thymidine kinase (J2R) and ribonucleotide reductase (I4L) genes and carrying a green fluorescent protein gene (VVTK-RR-/GFP), against malignant pleural mesothelioma. Twenty-two human mesothelioma cell lines, established in the authors' laboratory from patients' pleural effusions, were infected at multiplicities of infection of 0.01 and 0.1. All 22 lines were infected, showed significant Annexin V staining at 48 h, and after four days showed morbidity leading to cell death; maximum fluorescence differed between lines. Infectious virus production was detected in all 8 cell lines tested, described as low (Meso11, -163, -225), medium (Meso13, -45, -173) and high (Meso4, -34). In twenty NOD SCID mice given 5 x 10^6 Meso163 cells intraperitoneally and then PBS or 1 x 10^7 PFU of the virus, mean survival was 33 days with PBS and 55 days with the virus (p = 0.0001, Mantel-Cox), with fewer tumour deposits at autopsy. The authors concluded this virus may be a promising oncolytic virus for mesothelioma immunotherapy. Asbestos appears only in the introduction, where the authors describe mesothelioma as usually associated with chronic asbestos exposure, mainly during occupational activities.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: in vitro infection of human mesothelioma cell lines plus a mouse xenograft treatment experiment
• Who was studied: 22 human malignant pleural mesothelioma cell lines established from patients' pleural effusions in the authors' laboratory (Nantes, France), and 20 six-week-old female NOD SCID mice bearing intraperitoneal Meso163 human mesothelioma tumours
• Exposure: Attenuated recombinant vaccinia virus VVTK-RR-/GFP (Copenhagen strain, deleted in TK and RR genes, expressing GFP), at MOI 0.01 and 0.1 in vitro and a single intraperitoneal injection of 1 x 10^7 PFU in mice
• Main results:
  • All 22 mesothelioma cell lines were infected by the virus, and after 4 days all showed morbidity leading to cell death
  • Significant Annexin V staining was seen in all 22 cell lines 48 h after infection
  • Virus replication was detected in all 8 cell lines tested, low in Meso11, -163 and -225, medium in Meso13, -45 and -173, and high in Meso4 and -34
  • In the mouse experiment, mean survival was 33 days for PBS-treated mice versus 55 days for virus-treated mice
  • In a preliminary toxicity experiment in 3 NOD SCID mice, 1 x 10^7 PFU was not toxic while 1 x 10^8 PFU was lethal
  • At autopsy, PBS-treated mice had numerous metastases while virus-treated animals had no more than three massive tumours
• The authors' conclusion: The authors concluded that this double-deleted vaccinia virus may be a promising oncolytic virus for the oncolytic immunotherapy of malignant pleural mesothelioma
• Limitations the authors state:
  • The authors noted the virus did not completely cure the mice, possibly because these immunodeficient mice lack an adaptive immune system that would enhance oncolytic efficacy
  • GFP fluorescence from infected cells interfered with propidium iodide staining and could not be compensated
  • The initial toxicity experiment used only three mice and its data are not shown

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Pleura, Immunotherapy, Tumor Burden.

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