Interleukin-13 displaying retargeted oncolytic measles virus strains have significant activity against gliomas with improved specificity.
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.
Allen
Cory
C
Molecular Medicine Department, Mayo Clinic College Of Medicine, Rochester, Minnesota 55905, USA.
Paraskevakou
Georgia
G
Iankov
Ianko
I
Giannini
Caterina
C
Schroeder
Mark
M
Sarkaria
Jann
J
Schroeder
Mark
M
Puri
Raj K
RK
Russell
Stephen J
SJ
Galanis
Evanthia
E
D000818:Animals; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D002490:Central Nervous System / Q000378:metabolism / Q000821:virology; D002522:Chlorocebus aethiops; D005434:Flow Cytometry; D015316:Genetic Therapy; D005910:Glioma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000276:immunology; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism*; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000235:genetics / Q000627:therapeutic use*; D008457:Measles / Q000235:genetics / Q000276:immunology / Q000628:therapy; D008459:Measles virus / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019590:Nucleocapsid Proteins / Q000378:metabolism; D050130:Oncolytic Virotherapy; D014407:Tumor Cells, Cultured; D014709:Vero Cells; D023041:Xenograft Model Antitumor Assays
D018793:Interleukin-13; D053663:Interleukin-13 Receptor alpha2 Subunit; D019590:Nucleocapsid Proteins; D049452:Green Fluorescent Proteins