Targeted therapy of human glioblastoma combining the oncolytic properties of parvovirus H-1 and attenuated strains of the vaccinia virus

Both vaccinia virus and rat parvovirus H-1 are currently used to create drugs that have demonstrated their effectiveness against a number of human tumors. In preclinical studies it was demonstrated that the main factor responsible for the oncolytic activity of parvovirus H-1 is the NS1 protein and tumor cells of the brain were especially susceptible to its direct cytotoxic effect. We used NS1 gene insertion to arm two attenuated strains of vaccinia virus for virotherapy of glioblastoma: VV-NS1-dGF and MVA-NS1. Recombinant VV-NS1-dGF was engineered from replicative-competent L-IVP strain attenuated by deletion of the virus growth factor gene. MVA-NS1 was engineered from highly attenuated MVA strain, which is replicative-incompetent for mammalian cells. The NS1 transgene expression significantly enhanced the lytic activity of both recombinants against human U87MG glioblastoma cells regardless of the level of attenuation of the original virus strains in vitro. However, in in vivo experiments, the recombinant VV-NS1-dGF more effectively destroys the subcutaneous xenografts of U87MG cells in Nu/Nu mice compared with the strain MVA-NS1 after a single injection of viruses into the tumor region. Both recombinants selectively replicate in tumor cells, but reproductive capacity of the VV-NS1-dGF is higher, which ensures its rapid accumulation in xenografts and their subsequent destruction. Investigation of the antitumor properties of recombinants in the orthotopic model of U87MG human glioblastoma demonstrated an increase in the lifetime of mice and a significant decrease in tumor volume when treated with VV-NS1-dGF. The data obtained demonstrate that recombinant VV-NS1-dGF has good therapeutic potential against human glioblastoma.