Scientific Publications by FDA Staff

Mol Ther 2008 Sep;16(9):1556-64

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

Allen C, Paraskevakou G, Iankov I, Giannini C, Schroeder M, Sarkaria J, Schroeder M, Puri RK, Russell SJ, Galanis E

Galanis, E, Mayo Clin, Coll Med, Div Med Oncol, Dept Mol Med, 200 1st St SW, Rochester, MN 55905 USA Mayo Clin, Coll Med, Div Med Oncol, Dept Mol Med, Rochester, MN 55905 USA Mayo Clin, Coll Med, Div Anat Pathol, Rochester, MN 55905 USA US FDA, Rockville, MD 20857 USA Mayo Clin, Coll Med, Dept Oncol, Rochester, MN 55905 USA

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.