Evaluation of an attenuated vesicular stomatitis virus vector expressing interferon-β for use in malignant pleural mesothelioma

Heterogeneity in interferon responsiveness defines potential efficacy

Vassiliki Saloura, Liang Chuan S Wang, Zvi G. Fridlender, Jing Sun, Guanjun Cheng, Veena Kapoor, Daniel H. Sterman, Ronald N. Harty, Atsushi Okumura, Glen N Barber, Richard G. Vile, Mark J. Federspiel, Stephen J. Russell, Leslie Litzky, Steven M. Albelda

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Vesicular stomatitis virus (VSV) has shown promise as an oncolytic agent, although unmodified VSV can be neurotoxic. To avoid toxicity, a vector was created by introducing the interferon-β (IFN-β) gene (VSV.IFN-β). We conducted this study to determine the ability of VSV.IFN-β to lyse human cancer (mesothelioma) cells and to evaluate the potential of this recombinant virus for clinical translation. Four normal human mesothelial and 12 mesothelioma cell lines were tested for their susceptibility to VSV vectors in vitro. VSV.hIFN-β did not cause cytotoxicity in any normal lines. Only 4 of 12 lines were effectively lysed by VSV.hIFN-β. In the eight resistant lines, pretreatment with IFN-β prevented lysis of cells by VSV.GFP, and VSV infection or addition of IFN-β protein resulted in the upregulation of double-stranded RNA-dependent protein kinase (PKR), myxovirus resistance A (MxA), and 2′,5′-oligo-adenylate-synthetase (2′5′-OAS) mRNA. In the susceptible lines, there was no protection by pretreatment with IFN-β protein and no IFN-or VSV-induced changes in PKR, MxA, and 2′5′-OAS mRNA. This complete lack of IFN responsiveness could be explained by marked downregulation of interferon alpha receptors (IFNARs), p48, and PKR in both the mesothelioma cell lines and primary tumor biopsies screened. Presence of p48 in three tumor samples predicted responsiveness to IFN. Our data indicate that many mesothelioma tumors have partially intact IFN pathways that may affect the efficacy of oncolytic virotherapy. However, it may be feasible to prescreen individual susceptibility to VSV.IFN-β by immunostaining for the presence of p48 protein.

Original languageEnglish
Pages (from-to)51-64
Number of pages14
JournalHuman Gene Therapy
Volume21
Issue number1
DOIs
StatePublished - Jan 1 2010

Fingerprint

Vesicular Stomatitis
Interferons
Viruses
Mesothelioma
eIF-2 Kinase
Ligases
Orthomyxoviridae
Malignant Mesothelioma
Oncolytic Virotherapy
Interferon alpha-beta Receptor
Neoplasms
Messenger RNA
Proteins
Double-Stranded RNA
Virus Diseases
Tumor Cell Line
Up-Regulation
Down-Regulation

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Evaluation of an attenuated vesicular stomatitis virus vector expressing interferon-β for use in malignant pleural mesothelioma : Heterogeneity in interferon responsiveness defines potential efficacy. / Saloura, Vassiliki; Wang, Liang Chuan S; Fridlender, Zvi G.; Sun, Jing; Cheng, Guanjun; Kapoor, Veena; Sterman, Daniel H.; Harty, Ronald N.; Okumura, Atsushi; Barber, Glen N; Vile, Richard G.; Federspiel, Mark J.; Russell, Stephen J.; Litzky, Leslie; Albelda, Steven M.

In: Human Gene Therapy, Vol. 21, No. 1, 01.01.2010, p. 51-64.

Research output: Contribution to journalArticle

Saloura, V, Wang, LCS, Fridlender, ZG, Sun, J, Cheng, G, Kapoor, V, Sterman, DH, Harty, RN, Okumura, A, Barber, GN, Vile, RG, Federspiel, MJ, Russell, SJ, Litzky, L & Albelda, SM 2010, 'Evaluation of an attenuated vesicular stomatitis virus vector expressing interferon-β for use in malignant pleural mesothelioma: Heterogeneity in interferon responsiveness defines potential efficacy', Human Gene Therapy, vol. 21, no. 1, pp. 51-64. https://doi.org/10.1089/hum.2009.088
Saloura, Vassiliki ; Wang, Liang Chuan S ; Fridlender, Zvi G. ; Sun, Jing ; Cheng, Guanjun ; Kapoor, Veena ; Sterman, Daniel H. ; Harty, Ronald N. ; Okumura, Atsushi ; Barber, Glen N ; Vile, Richard G. ; Federspiel, Mark J. ; Russell, Stephen J. ; Litzky, Leslie ; Albelda, Steven M. / Evaluation of an attenuated vesicular stomatitis virus vector expressing interferon-β for use in malignant pleural mesothelioma : Heterogeneity in interferon responsiveness defines potential efficacy. In: Human Gene Therapy. 2010 ; Vol. 21, No. 1. pp. 51-64.
@article{3ba87211b5994f2293096accf36e2123,
title = "Evaluation of an attenuated vesicular stomatitis virus vector expressing interferon-β for use in malignant pleural mesothelioma: Heterogeneity in interferon responsiveness defines potential efficacy",
abstract = "Vesicular stomatitis virus (VSV) has shown promise as an oncolytic agent, although unmodified VSV can be neurotoxic. To avoid toxicity, a vector was created by introducing the interferon-β (IFN-β) gene (VSV.IFN-β). We conducted this study to determine the ability of VSV.IFN-β to lyse human cancer (mesothelioma) cells and to evaluate the potential of this recombinant virus for clinical translation. Four normal human mesothelial and 12 mesothelioma cell lines were tested for their susceptibility to VSV vectors in vitro. VSV.hIFN-β did not cause cytotoxicity in any normal lines. Only 4 of 12 lines were effectively lysed by VSV.hIFN-β. In the eight resistant lines, pretreatment with IFN-β prevented lysis of cells by VSV.GFP, and VSV infection or addition of IFN-β protein resulted in the upregulation of double-stranded RNA-dependent protein kinase (PKR), myxovirus resistance A (MxA), and 2′,5′-oligo-adenylate-synthetase (2′5′-OAS) mRNA. In the susceptible lines, there was no protection by pretreatment with IFN-β protein and no IFN-or VSV-induced changes in PKR, MxA, and 2′5′-OAS mRNA. This complete lack of IFN responsiveness could be explained by marked downregulation of interferon alpha receptors (IFNARs), p48, and PKR in both the mesothelioma cell lines and primary tumor biopsies screened. Presence of p48 in three tumor samples predicted responsiveness to IFN. Our data indicate that many mesothelioma tumors have partially intact IFN pathways that may affect the efficacy of oncolytic virotherapy. However, it may be feasible to prescreen individual susceptibility to VSV.IFN-β by immunostaining for the presence of p48 protein.",
author = "Vassiliki Saloura and Wang, {Liang Chuan S} and Fridlender, {Zvi G.} and Jing Sun and Guanjun Cheng and Veena Kapoor and Sterman, {Daniel H.} and Harty, {Ronald N.} and Atsushi Okumura and Barber, {Glen N} and Vile, {Richard G.} and Federspiel, {Mark J.} and Russell, {Stephen J.} and Leslie Litzky and Albelda, {Steven M.}",
year = "2010",
month = "1",
day = "1",
doi = "10.1089/hum.2009.088",
language = "English",
volume = "21",
pages = "51--64",
journal = "Human Gene Therapy",
issn = "1043-0342",
publisher = "Mary Ann Liebert Inc.",
number = "1",

}

TY - JOUR

T1 - Evaluation of an attenuated vesicular stomatitis virus vector expressing interferon-β for use in malignant pleural mesothelioma

T2 - Heterogeneity in interferon responsiveness defines potential efficacy

AU - Saloura, Vassiliki

AU - Wang, Liang Chuan S

AU - Fridlender, Zvi G.

AU - Sun, Jing

AU - Cheng, Guanjun

AU - Kapoor, Veena

AU - Sterman, Daniel H.

AU - Harty, Ronald N.

AU - Okumura, Atsushi

AU - Barber, Glen N

AU - Vile, Richard G.

AU - Federspiel, Mark J.

AU - Russell, Stephen J.

AU - Litzky, Leslie

AU - Albelda, Steven M.

PY - 2010/1/1

Y1 - 2010/1/1

N2 - Vesicular stomatitis virus (VSV) has shown promise as an oncolytic agent, although unmodified VSV can be neurotoxic. To avoid toxicity, a vector was created by introducing the interferon-β (IFN-β) gene (VSV.IFN-β). We conducted this study to determine the ability of VSV.IFN-β to lyse human cancer (mesothelioma) cells and to evaluate the potential of this recombinant virus for clinical translation. Four normal human mesothelial and 12 mesothelioma cell lines were tested for their susceptibility to VSV vectors in vitro. VSV.hIFN-β did not cause cytotoxicity in any normal lines. Only 4 of 12 lines were effectively lysed by VSV.hIFN-β. In the eight resistant lines, pretreatment with IFN-β prevented lysis of cells by VSV.GFP, and VSV infection or addition of IFN-β protein resulted in the upregulation of double-stranded RNA-dependent protein kinase (PKR), myxovirus resistance A (MxA), and 2′,5′-oligo-adenylate-synthetase (2′5′-OAS) mRNA. In the susceptible lines, there was no protection by pretreatment with IFN-β protein and no IFN-or VSV-induced changes in PKR, MxA, and 2′5′-OAS mRNA. This complete lack of IFN responsiveness could be explained by marked downregulation of interferon alpha receptors (IFNARs), p48, and PKR in both the mesothelioma cell lines and primary tumor biopsies screened. Presence of p48 in three tumor samples predicted responsiveness to IFN. Our data indicate that many mesothelioma tumors have partially intact IFN pathways that may affect the efficacy of oncolytic virotherapy. However, it may be feasible to prescreen individual susceptibility to VSV.IFN-β by immunostaining for the presence of p48 protein.

AB - Vesicular stomatitis virus (VSV) has shown promise as an oncolytic agent, although unmodified VSV can be neurotoxic. To avoid toxicity, a vector was created by introducing the interferon-β (IFN-β) gene (VSV.IFN-β). We conducted this study to determine the ability of VSV.IFN-β to lyse human cancer (mesothelioma) cells and to evaluate the potential of this recombinant virus for clinical translation. Four normal human mesothelial and 12 mesothelioma cell lines were tested for their susceptibility to VSV vectors in vitro. VSV.hIFN-β did not cause cytotoxicity in any normal lines. Only 4 of 12 lines were effectively lysed by VSV.hIFN-β. In the eight resistant lines, pretreatment with IFN-β prevented lysis of cells by VSV.GFP, and VSV infection or addition of IFN-β protein resulted in the upregulation of double-stranded RNA-dependent protein kinase (PKR), myxovirus resistance A (MxA), and 2′,5′-oligo-adenylate-synthetase (2′5′-OAS) mRNA. In the susceptible lines, there was no protection by pretreatment with IFN-β protein and no IFN-or VSV-induced changes in PKR, MxA, and 2′5′-OAS mRNA. This complete lack of IFN responsiveness could be explained by marked downregulation of interferon alpha receptors (IFNARs), p48, and PKR in both the mesothelioma cell lines and primary tumor biopsies screened. Presence of p48 in three tumor samples predicted responsiveness to IFN. Our data indicate that many mesothelioma tumors have partially intact IFN pathways that may affect the efficacy of oncolytic virotherapy. However, it may be feasible to prescreen individual susceptibility to VSV.IFN-β by immunostaining for the presence of p48 protein.

UR - http://www.scopus.com/inward/record.url?scp=74949142894&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=74949142894&partnerID=8YFLogxK

U2 - 10.1089/hum.2009.088

DO - 10.1089/hum.2009.088

M3 - Article

VL - 21

SP - 51

EP - 64

JO - Human Gene Therapy

JF - Human Gene Therapy

SN - 1043-0342

IS - 1

ER -