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

Cory Allen, Georgia Paraskevakou, Ianko Iankov, Caterina Giannini, Mark Schroeder, Jann Sarkaria, Mark Schroeder, Raj K. Puri, Stephen J. Russell, Evanthia Galanis

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

The majority of glioblastoma multiforme (GBM) tumors (80%) overexpress interleukin-13 receptor α2 (IL-13Rα2), but there is no expression of IL-13Rα2 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-13Rα2. MV-GFP-HAA-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-13Rα2 overexpressing glioma lines, and lack of CPE/viral replication in normal human astrocytes and normal human fibroblasts not expressing IL-13Rα2. 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 Ifnarko CD46 Ge mice resulted in lack of neurotoxicity. Strains of measles virus retargeted against the glioma-specific IL-13Rα2 receptor have comparable therapeutic efficacy, and improved specificity as compared with the unmodified measles virus strain MV-GFP in vitro and in vivo.

Original languageEnglish (US)
Pages (from-to)1556-1564
Number of pages9
JournalMolecular Therapy
Volume16
Issue number9
DOIs
StatePublished - 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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