Type I interferon-sensitive recombinant newcastle disease virus for oncolytic virotherapy.
Newcastle disease virus (NDV), an avian paramyxovirus, is tumor selective and intrinsically oncolytic because of its potent ability to induce apoptosis. Several studies have demonstrated that NDV is selectively cytotoxic to tumor cells but not normal cells due to defects in the interferon (IFN) antiviral responses of tumor cells. Many naturally occurring strains of NDV have an intact IFN-antagonistic function and can still replicate in normal human cells. To avoid potential toxicity issues with NDV, especially in cancer patients with immunosuppression, safe NDV-oncolytic vectors are needed. We compared the cell killing abilities of (i) a recombinant NDV (rNDV) strain, Beaudette C, containing an IFN-antagonistic, wild-type V protein (rBC), (ii) an isogenic recombinant virus with a mutant V protein (rBC-Edit virus) that induces increased IFN in infected cells and whose replication is restricted in normal human cells, and (iii) a recombinant LaSota virus with a virulent F protein cleavage site that is as interferon sensitive as rBC-Edit virus (LaSota V.F. virus). Our results indicated that the tumor-selective replication of rNDV is determined by the differential regulation of IFN-alpha and downstream antiviral genes induced by IFN-alpha, especially through the IRF-7 pathway. In a nude mouse model of human fibrosarcoma, we show that the IFN-sensitive NDV variants are as effective as IFN-resistant rBC virus in clearing the tumor burden. In addition, mice treated with rNDV exhibited no signs of toxicity to the viruses. These findings indicate that augmentation of innate immune responses by NDV results in selective oncolysis and offer a novel and safe virotherapy platform.
Center for Molecular Medicine and Infectious Diseases, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, 1981 Kraft Drive, Blacksburg, VA 24061, USA. kumarans@vt.edu
Subbiah
S
Elankumaran
Vrushali
V
Chavan
Dan
D
Qiao
Raghunath
R
Shobana
Gopakumar
G
Moorkanat
Moanaro
M
Biswas
Siba K
SK
Samal
D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D005354:Fibrosarcoma / Q000473:pathology / Q000628:therapy; D006801:Humans; D007370:Interferon Type I / Q000037:antagonists & inhibitors / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009522:Newcastle disease virus / Q000235:genetics / Q000276:immunology*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics / Q000276:immunology*; D011995:Recombination, Genetic; D014764:Viral Proteins / Q000235:genetics* / Q000276:immunology
C070065:36 kDa V protein, Newcastle disease virus; D007370:Interferon Type I; D014764:Viral Proteins