Interleukin-13 Displaying Retargeted Oncolytic Measles Virus Strains Have Significant Activity Against Gliomas With Improved Specificity

Molecular Medicine Department, Mayo Clinic College Of Medicine, Rochester, Minnesota 55905, USA.
Molecular Therapy (Impact Factor: 6.23). 10/2008; 16(9):1556-64. DOI: 10.1038/mt.2008.152
Source: PubMed


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.

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Available from: Mark A Schroeder, May 19, 2014
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    • "Subsequent display of measles H and F on the surface of infected cells then initiates fusion between neighboring cells, ultimately resulting in large multinucleated syncytia. Recently, a number of groups have altered the tropism of measles virus via addition of peptides [17], growth factors [18], single chain antibodies (scFv) [19] or cytokines [20] to the carboxyl-terminus of the hemagglutinin protein. The primary application of this technology has been the creation of oncolytic measles viruses, which are capable of specifically recognizing, infecting and killing tumor cells. "
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    PLoS ONE 10/2011; 6(10):e26381. DOI:10.1371/journal.pone.0026381 · 3.23 Impact Factor
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    • "Pancreatic tumors were also successfully targeted by IL-13-PE in an animal model of human cancer [15,16]. Thus, IL-13Rα2 is currently being assessed as a cancer therapy in a variety of preclinical and clinical trials [4,17,18] "
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