Engineered measles virus as a novel oncolytic viral therapy system for hepatocellular carcinoma.
The oncolytic measles virus Edmonston strain (MV-Edm), a nonpathogenic virus targeting cells expressing abundant CD46, selectively destroys neoplastic tissue. Clinical development of MV-Edm would benefit from noninvasive monitoring strategies to determine the speed and extent of the spread of the virus in treated patients and the location of virus-infected cells. We evaluated recombinant MV-Edm expressing carcinoembryonic antigen (CEA) or the human sodium iodide symporter (hNIS) for oncolytic potential in hepatocellular carcinoma (HCC) and efficiency in tracking viruses in vivo by noninvasive monitoring. CD46 expression in human HCC and primary hepatocytes was assessed by flow cytometry and immunohistochemistry. Infectivity, syncytium formation, and cytotoxicity of recombinant MV-Edm in HCC cell lines were evaluated by fluorescence microscopy, crystal violet staining, and the MTS assay. Transgene expression in HCC cell lines after infection with recombinant MV-Edm in vitro and in vivo was assessed by CEA concentration, 125I-uptake, and 123I-imaging studies. Toxicology studies were performed in Ifnar(KO)xCD46 transgenic mice. The CD46 receptor was highly expressed in HCC compared to nonmalignant hepatic tissue. Recombinant MV-Edm efficiently infected HCC cell lines, resulting in extensive syncytium formation followed by cell death. Transduction of HCC cell lines and subcutaneous HCC xenografts with recombinant MV-Edm resulted in high-level expression of transgenes in vitro and in vivo. MV-Edm was nontoxic in susceptible mice. Intratumoral and intravenous therapy with recombinant MV-Edm resulted in inhibition of tumor growth and prolongation of survival with complete tumor regression in up to one third of animals. In conclusion, engineered MV-Edm may be a potent and novel cancer gene therapy system for HCC. MV-Edm expressing CEA or hNIS elicited oncolytic effects in human HCC cell lines in vitro and in vivo, enabling the spread of the virus to be monitored in a noninvasive manner.
Blechacz
Boris
B
Molecular Medicine Program, Mayo Clinic, Rochester, MN 55905, USA.
Splinter
Patrick L
PL
Greiner
Suzanne
S
Myers
Rae
R
Peng
Kah-Whye
KW
Federspiel
Mark J
MJ
Russell
Stephen J
SJ
LaRusso
Nicholas F
NF
D000818:Animals; D002272:Carcinoembryonic Antigen / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000628:therapy*; D003588:Cytopathogenic Effect, Viral; D005260:Female; D005818:Genetic Engineering / Q000379:methods; D006801:Humans; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes / Q000378:metabolism; D008113:Liver Neoplasms / Q000628:therapy*; D008297:Male; D008458:Measles Vaccine / Q000235:genetics; D008459:Measles virus / Q000235:genetics* / Q000276:immunology; D051916:Membrane Cofactor Protein / Q000096:biosynthesis; D051379:Mice; D009368:Neoplasm Transplantation; D050130:Oncolytic Virotherapy / Q000379:methods*; D027981:Symporters / Q000235:genetics; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000099209:Sodium-Iodide Symporters
D002272:Carcinoembryonic Antigen; D007457:Iodine Radioisotopes; D008458:Measles Vaccine; D051916:Membrane Cofactor Protein; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C497857:CD46 protein, human