Oncolytic measles viruses encoding interferon beta and the thyroidal sodium iodide symporter gene for mesothelioma virotherapy

Our plain-English summary of Oncolytic measles viruses encoding interferon beta and the thyroidal sodium iodide symporter gene for mesothelioma virotherapy, by H. Li, K.W. Peng, D. Dingli, et al (Cancer Gene Therapy, 2010).

The study

• Authors: H. Li, K.W. Peng, D. Dingli, R.A. Kratzke, S.J. Russell
• Journal: Cancer Gene Therapy
• Published: 2010;17(8):550-8
• Cited by: 104 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelioma usually leads to death within 8-14 months of diagnosis. To increase the potency of oncolytic measles viruses (MVs) for mesothelioma therapy, we inserted the interferon beta (IFNbeta) gene alone or with the human thyroidal sodium iodide symporter (NIS) gene into attenuated MV of the Edmonston lineage. The corresponding mouse IFNbeta (mIFNbeta) viruses, MV-mIFNbeta and MV-mIFNbeta-NIS, successfully propagated in human mesothelioma cells, leading to intercellular fusion and cell death. High levels of mIFNbeta were detected in the supernatants of the infected cells, and radioiodine uptake was substantial in the cells infected with MV-mIFNbeta-NIS. MV with mIFNbeta expression triggered CD68-positive immune cell infiltration 2-4 times higher than MV-GFP injected into the tumor site. The numbers of CD31-positive vascular endothelial cells within the tumor were decreased at day 7 after intratumoral injection of MV-mIFNbeta or MV-mIFNbeta-NIS, but not after MV-GFP and PBS administration. Immunohistochemical analysis showed that MV-mIFNbeta changed the microenvironment of the mesothelioma by increasing innate immune cell infiltration and inhibiting tumor angiogenesis. Oncolytic MVs coding for IFNbeta effectively retarded growth of human mesotheliomas and prolonged survival time in several mesothelioma tumor models. The results suggest that oncolytic MVs that code for IFNbeta and NIS will be potent and versatile agents for the treatment of human mesothelioma.

In plain English

This laboratory and mouse study tested oncolytic measles viruses (MVs) of the Edmonston lineage carrying the mouse interferon beta (mIFNbeta) gene alone or with the human thyroidal sodium iodide symporter (NIS) gene. Human mesothelioma cell lines H2596, H2373, H513, M30 and MSTO-211H were infected in culture and all formed syncytia; the viruses replicated in M30 and H513 cells with high mIFNbeta in the supernatants, and H513 and H2373 cells infected with NIS-carrying viruses took up radioiodine, which potassium perchlorate blocked, whereas cells infected with MV-mIFNbeta did not. Mice bearing H513 flank tumours were injected intratumorally; nude mice with H2373 peritoneal tumours received virus into the peritoneum. In nude mice with H513 flank tumours, median survival from tumour engraftment was 20 days with PBS, 45 days with MV-GFP or MV-GFP-NIS, 65 days with MV-mIFNbeta and 60 days with MV-mIFNbeta-NIS. In H513 tumour sections, MV-mIFNbeta gave CD68-positive infiltration 2-4 times higher than the other MVs at day 7, and CD31 vascular density differed significantly from MV-GFP at days 4 and 7. The authors concluded that mIFNbeta-expressing MVs increased innate immune cell infiltration and inhibited tumour angiogenesis more efficiently than the parental virus, while NIS permitted noninvasive imaging of virus spread.

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 cell culture experiments with engineered measles viruses plus mouse xenograft (animal) experiments
• Who was studied: Human mesothelioma cell lines in culture (H2596, H2373, H513, M30, MSTO-211H infected; REN also maintained), and nude (athymic nu/nu) and C.B-17-SCID mice bearing H513 subcutaneous tumours or H2373 peritoneal tumours; immunohistochemistry on 3 mice per group per time point
• Exposure: Attenuated measles viruses of the Edmonston lineage engineered to express mouse interferon beta alone (MV-mIFNbeta) or with the sodium iodide symporter (MV-mIFNbeta-NIS), compared with MV-GFP, MV-GFP-NIS and PBS; given in vitro at MOI 0.1 or 1.0 and in mice intratumorally or into the peritoneum
• Main results:
  • All five mesothelioma cell lines infected in culture were susceptible to MV infection and formed syncytia
  • In M30 and H513 cells infected at MOI 1.0, all the viruses propagated and high mIFNbeta levels were detected in supernatants after MV-mIFNbeta or MV-mIFNbeta-NIS infection
  • H513 and H2373 cells infected with NIS-carrying viruses took up radioiodine, uptake was blocked by potassium perchlorate, and cells infected with MV-mIFNbeta did not concentrate radioiodine
  • In H513 tumours in nude mice given PBS, MV-GFP or MV-mIFNbeta intratumorally, MV with mIFNbeta expression gave CD68-positive immune cell infiltration 2-4 times higher than the other MVs at day 7
  • Vascular density (CD31 staining) in MV-mIFNbeta-treated H513 tumours differed significantly from MV-GFP-treated tumours at days 4 and 7
  • In nude mice with H513 flank tumours, median survival after tumour engraftment was 20 days for PBS controls and 45 days for mice receiving MV-GFP (also MV-GFP-NIS)
  • In the same nude mouse H513 flank model, median survival was 65 days with MV-mIFNbeta and 60 days with MV-mIFNbeta-NIS (reported as P less than 0.001)
  • In SCID mice given MV-GFP-NIS or MV-mIFNbeta-NIS, tumours concentrated radioiodine and virus gene expression was visible on imaging at day 7; no signal was seen with MV-GFP or MV-mIFNbeta
  • In nude mice with H2373 peritoneal tumours given virus into the peritoneum, MV-mIFNbeta extended survival
• The authors' conclusion: The authors concluded that in rodent mesothelioma models MVs expressing mIFNbeta increased innate immune cell infiltration and inhibited tumour angiogenesis more efficiently than the parental virus, that the IFN transgene enhanced therapeutic activity, and that the NIS transgene allowed noninvasive monitoring of virus spread
• Limitations the authors state:
  • The authors noted that interferon beta would presumably interfere with measles virus replication more severely in immunocompetent mice than in the immunodeficient mice used here
  • The authors noted that immune responses induced by mIFNbeta may cause faster viral clearance as well as antitumour effects

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Angiogenesis.

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