Evaluation of an attenuated vesicular stomatitis virus vector expressing interferon-beta 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-beta (IFN-beta) gene (VSV.IFN-beta). We conducted this study to determine the ability of VSV.IFN-beta 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-beta did not cause cytotoxicity in any normal lines. Only 4 of 12 lines were effectively lysed by VSV.hIFN-beta. In the eight resistant lines, pretreatment with IFN-beta prevented lysis of cells by VSV.GFP, and VSV infection or addition of IFN-beta 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-beta 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-beta by immunostaining for the presence of p48 protein.
Saloura
Vassiliki
V
Thoracic Oncology Research Laboratory, University of Pennsylvania Medical Center , Philadelphia, PA 19104, USA.
Wang
Liang-Chuan S
LC
Fridlender
Zvi G
ZG
Sun
Jing
J
Cheng
Guanjun
G
Kapoor
Veena
V
Sterman
Daniel H
DH
Harty
Ronald N
RN
Okumura
Atsushi
A
Barber
Glen N
GN
Vile
Richard G
RG
Federspiel
Mark J
MJ
Russell
Stephen J
SJ
Litzky
Leslie
L
Albelda
Steven M
SM
D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018740:Genetic Heterogeneity / Q000187:drug effects; D005822:Genetic Vectors / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D016899:Interferon-beta / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D008654:Mesothelioma / Q000235:genetics* / Q000473:pathology / Q000628:therapy* / Q000821:virology; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000378:metabolism; D050130:Oncolytic Virotherapy / Q000379:methods*; D010997:Pleural Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D018116:Vesiculovirus / Q000235:genetics* / Q000502:physiology; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects
D009363:Neoplasm Proteins; D012333:RNA, Messenger; D049452:Green Fluorescent Proteins; D016899:Interferon-beta