Interleukin-13 displaying retargeted oncolytic measles virus strains have significant activity against gliomas with improved specificity.

Abstract

The majority of glioblastoma multiforme (GBM) tumors (80%) overexpress interleukin-13 receptor alpha2 (IL-13Ralpha2), but there is no expression of IL-13Ralpha2 in normal brain. Vaccine strains of measles virus have significant antitumor activity against gliomas. We tested the hypothesis that measles virus entry could be retargeted via the IL-13Ralpha2. MV-GFP-H(AA)-IL-13 was generated from the Edmonston-NSe vaccine strain, by displaying human IL-13 at the C-terminus of the H protein, and introducing CD46 and signaling lymphocyte activation molecule (SLAM)-ablating mutations in H. The IL-13 retargeted virus showed significant cytopathic effect (CPE) against IL-13Ralpha2 overexpressing glioma lines, and lack of CPE/viral replication in normal human astrocytes and normal human fibroblasts not expressing IL-13Ralpha2. In vivo treatment of orthotopically implanted GBM12 xenografts demonstrated significant prolongation of survival in mice treated with the retargeted strain (P < 0.0001), and comparable activity between the IL-13R retargeted strain and MV-GFP (P = 0.6377). In contrast to MV-GFP-treated mice, administration of the retargeted strain in the central nervous system of measles replication-permissive Ifnar(ko) CD46 Ge mice resulted in lack of neurotoxicity. Strains of measles virus retargeted against the glioma-specific IL-13Ralpha2 receptor have comparable therapeutic efficacy, and improved specificity as compared with the unmodified measles virus strain MV-GFP in vitro and in vivo.

• Authors: Cory Allen, Georgia Paraskevakou, Ianko Iankov, Caterina Giannini, Mark Schroeder, Jann Sarkaria, Mark Schroeder, Raj K Puri, Stephen J Russell, Evanthia Galanis
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 16 Issue 9 Pg. 1556-64 (Sep 2008) ISSN: 1525-0024 [Electronic] United States
• PMID: 18665158 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Interleukin-13
• Interleukin-13 Receptor alpha2 Subunit
• Nucleocapsid Proteins
• Green Fluorescent Proteins

Topics

• Animals
• Blotting, Western
• Brain Neoplasms (genetics, immunology, therapy)
• Central Nervous System (metabolism, virology)
• Chlorocebus aethiops
• Flow Cytometry
• Genetic Therapy
• Glioma (genetics, immunology, therapy)
• Green Fluorescent Proteins (genetics, immunology)
• Humans
• Interleukin-13 (metabolism)
• Interleukin-13 Receptor alpha2 Subunit (genetics, therapeutic use)
• Measles (genetics, immunology, therapy)
• Measles virus (physiology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Nucleocapsid Proteins (metabolism)
• Oncolytic Virotherapy
• Tumor Cells, Cultured
• Vero Cells
• Xenograft Model Antitumor Assays