Intravenous injection of oncolytic picornavirus SVV-001 prolongs animal survival in a panel of primary tumor-based orthotopic xenograft mouse models of pediatric glioma.

Abstract

BACKGROUND:

Seneca Valley virus (SVV-001) is a nonpathogenic oncolytic virus that can be systemically administered and can pass through the blood-brain barrier. We examined its therapeutic efficacy and the mechanism of tumor cell infection in pediatric malignant gliomas.

METHODS:

In vitro antitumor activities were examined in primary cultures, preformed neurospheres, and self-renewing glioma cells derived from 6 patient tumor orthotopic xenograft mouse models (1 anaplastic astrocytoma and 5 GBM). In vivo therapeutic efficacy was examined by systemic treatment of preformed xenografts in 3 permissive and 2 resistant models. The functional role of sialic acid in mediating SVV-001 infection was investigated using neuraminidase and lectins that cleave or competitively bind to linkage-specific sialic acids.

RESULTS:

SVV-001 at a multiplicity of infection of 0.5 to 25 replicated in and effectively killed primary cultures, preformed neurospheres, and self-renewing stemlike single glioma cells derived from 4 of the 6 glioma models in vitro. A single i.v. injection of SVV-001 (5 × 10(12) viral particles/kg) led to the infection of orthotopic xenografts without harming normal mouse brain cells, resulting in significantly prolonged survival in all 3 permissive and 1 resistant mouse models (P < .05). Treatment with neuraminidase and competitive binding using lectins specific for α2,3-linked and/or α2,6-linked sialic acid significantly suppressed SVV-001 infectivity (P < .01).

CONCLUSION:

SVV-001 possesses strong antitumor activity against pediatric malignant gliomas and utilizes α2,3-linked and α2,6-linked sialic acids as mediators of tumor cell infection. Our findings support the consideration of SVV-001 for clinical trials in children with malignant glioma.

• Authors: Zhigang Liu, Xiumei Zhao, Hua Mao, Patricia A Baxter, Yulun Huang, Litian Yu, Lalita Wadhwa, Jack M Su, Adekunle Adesina, Lazlo Perlaky, Mary Hurwitz, Neeraja Idamakanti, Seshidhar Reddy Police, Paul L Hallenbeck, Richard L Hurwitz, Ching C Lau, Murali Chintagumpala, Susan M Blaney, Xiao-Nan Li
• Journal: Neuro-oncology (Neuro Oncol) Vol. 15 Issue 9 Pg. 1173-85 (Sep 2013) ISSN: 1523-5866 [Electronic] England
• PMID: 23658322 (Publication Type: Journal Article)

Chemical References

• N-Acetylneuraminic Acid

Topics

• Animals
• Brain Neoplasms (metabolism, therapy)
• Disease Models, Animal
• Glioma (metabolism, therapy)
• Injections, Intravenous
• Mice
• Mice, SCID
• N-Acetylneuraminic Acid (metabolism)
• Oncolytic Virotherapy
• Oncolytic Viruses
• Picornaviridae
• Survival Analysis
• Xenograft Model Antitumor Assays