Intravenously Administered Alphavirus Vector VA7 Eradicates Orthotopic Human Glioma Xenografts in Nude Mice

Abstract

BackgroundVA7 is a neurotropic alphavirus vector based on an attenuated strain of Semliki Forest virus. We have previously shown that VA7 exhibits oncolytic activity against human melanoma xenografts in immunodeficient mice. The purpose of this study was to determine if intravenously administered VA7 would be effective against human glioma.Methodology/Principal Findings In vitro, U87, U251, and A172 human glioma cells were infected and killed by VA7-EGFP. In vivo, antiglioma activity of VA7 was tested in Balb/c nude mice using U87 cells stably expressing firefly luciferase in subcutaneous and orthotopic tumor models. Intravenously administered VA7-EGFP completely eradicated 100% of small and 50% of large subcutaneous U87Fluc tumors. A single intravenous injection of either VA7-EGFP or VA7 expressing Renilla luciferase (VA7-Rluc) into mice bearing orthotopic U87Fluc tumors caused a complete quenching of intracranial firefly bioluminescence and long-term survival in total 16 of 17 animals. In tumor-bearing mice injected with VA7-Rluc, transient intracranial and peripheral Renilla bioluminescence was observed. Virus was well tolerated and no damage to heart, liver, spleen, or brain was observed upon pathological assessment at three and ninety days post injection, despite detectable virus titers in these organs during the earlier time point.ConclusionVA7 vector is apathogenic and can enter and destroy brain tumors in nude mice when administered systemically. This study warrants further elucidation of the mechanism of tumor destruction and attenuation of the VA7 virus.

Lapatinib-incorporated lipoprotein-like nanoparticles: preparation and a proposed breast cancer-targeting mechanism

“…Mice bearing BT-474 xenografts were established as described previously [8] . Briefly, 2×10 6 BT-474 cells/100 μL was injected into the right flank of a female CB-17 SCID mouse.…”

Alphavirus Vectors for Therapy of Neurological Disorders

“…Further development has included using oncolytic SFV vectors against lung cancer [26] and osteosarcoma [27] in mouse models. Recently, intravenous administration of oncolytic SFV-A7 provided therapeutic efficacy in nude mice with human glioma xenografts [28]. Furthermore, in the context of tumor therapy, SFV vectors have been encapsulated in liposomes to provide targeting of tumor tissue [29].…”

“…Additional encouragement was received from the confirmation of regression of human glioma xenografts in nude mice after intravenous administration [28]. One drawback with applying alphaviruses for therapeutic use is the relatively short duration of gene expression, due to the nature of non-integrating degradable RNA.…”

“…Treatment with 5 x 10e7 particles showed 70% reduction in tumor volume, whereas the higher dose of 5 x 10e8 particles generated an 87% reduction. Alphaviruses have also proven their excellent efficacy in CNS delivery after intravenous [28], intranasal [33] and intraperitoneal [34] administration, but their application in treating neurological disorders might to some extent be limited by the transient nature of expression. Therefore, other viruses such as adeno-associated viruses (AAV) and lentiviruses providing long-term expression profiles might be more suitable for these applications [2].…”

Small Animal Imaging in Development of New Generation Diagnostic and Therapeutic Agents

“…This method has successfully use i.e. in imaging of the therapeutic effect of the viruses in cancer (Heikkilä et al 2010). …”