Oncolytic measles viruses encoding interferon beta and the thyroidal sodium iodide symporter gene for mesothelioma virotherapy.
Mesothelioma usually leads to death within 8-14 months of diagnosis. To increase the potency of oncolytic measles viruses (MVs) for mesothelioma therapy, we inserted the interferon beta (IFNbeta) gene alone or with the human thyroidal sodium iodide symporter (NIS) gene into attenuated MV of the Edmonston lineage. The corresponding mouse IFNbeta (mIFNbeta) viruses, MV-mIFNbeta and MV-mIFNbeta-NIS, successfully propagated in human mesothelioma cells, leading to intercellular fusion and cell death. High levels of mIFNbeta were detected in the supernatants of the infected cells, and radioiodine uptake was substantial in the cells infected with MV-mIFNbeta-NIS. MV with mIFNbeta expression triggered CD68-positive immune cell infiltration 2-4 times higher than MV-GFP injected into the tumor site. The numbers of CD31-positive vascular endothelial cells within the tumor were decreased at day 7 after intratumoral injection of MV-mIFNbeta or MV-mIFNbeta-NIS, but not after MV-GFP and PBS administration. Immunohistochemical analysis showed that MV-mIFNbeta changed the microenvironment of the mesothelioma by increasing innate immune cell infiltration and inhibiting tumor angiogenesis. Oncolytic MVs coding for IFNbeta effectively retarded growth of human mesotheliomas and prolonged survival time in several mesothelioma tumor models. The results suggest that oncolytic MVs that code for IFNbeta and NIS will be potent and versatile agents for the treatment of human mesothelioma.
Li
H
H
Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Peng
K-W
KW
Dingli
D
D
Kratzke
R A
RA
Russell
S J
SJ
D000818:Animals; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics*; D007457:Iodine Radioisotopes; D008459:Measles virus / Q000235:genetics / Q000502:physiology*; D008654:Mesothelioma / Q000000981:diagnostic imaging / Q000628:therapy* / Q000821:virology; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D050130:Oncolytic Virotherapy / Q000379:methods*; D010957:Plasmids / Q000235:genetics; D027981:Symporters / Q000096:biosynthesis / Q000235:genetics*; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods; D014709:Vero Cells; D023041:Xenograft Model Antitumor Assays; D000099209:Sodium-Iodide Symporters
D016899:Interferon-beta; D007457:Iodine Radioisotopes; D027981:Symporters; D000099209:Sodium-Iodide Symporters