Dual therapy of ovarian cancer using measles viruses expressing carcinoembryonic antigen and sodium iodide symporter.
OBJECTIVE
MV-CEA is an oncolytic measles virus currently being tested in patients with ovarian cancer and whose propagation can be monitored by measuring blood carcinoembryonic antigen (CEA) levels. MV-NIS is an oncolytic measles virus coding for the thyroidal sodium iodide symporter (NIS) whose propagation can be mapped by serial radioiodine imaging. Expression of both CEA and NIS genes from a single virus would combine sensitive, quantitative expression monitoring (CEA) with radioisotopic expression mapping (NIS). Because of the unfavorable replication kinetics of measles viruses expressing both CEA and NIS, we explored the feasibility of combining MV-CEA with MV-NIS for comprehensive virotherapy monitoring in ovarian cancer.


RESULTS
Mice implanted with i.p. SKOV3ip.1 ovarian cancer xenografts received MV-CEA alone, MV-NIS alone, or a combination of MV-CEA plus MV-NIS. Viral gene expression was monitored by measuring blood CEA levels, and the location of virus-infected cells was monitored by gamma camera imaging. Surprisingly, mice receiving the combination of MV-CEA plus MV-NIS showed greatly superior responses to therapy, but this was associated with 10-fold lower plasma levels of CEA compared with mice treated with MV-CEA alone. In vitro studies showed superior replication kinetics of MV-NIS relative to MV-CEA. The gamma camera scans were considerably less sensitive than the plasma CEA marker for monitoring virus infection.


CONCLUSIONS
Dual therapy with MV-CEA and MV-NIS is superior to treatment with either virus alone, and it allows noninvasive monitoring of virotherapy via soluble marker peptide and gamma camera imaging. This has important implications for the clinical development of oncolytic measles viruses.
Molecular Medicine Program, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Kosei
K
Hasegawa
Linh
L
Pham
Michael K
MK
O'Connor
Mark J
MJ
Federspiel
Stephen J
SJ
Russell
Kah-Whye
KW
Peng
D000818:Animals; D002272:Carcinoembryonic Antigen / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D007700:Kinetics; D008459:Measles virus / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology; D010051:Ovarian Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D014709:Vero Cells; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D000099209:Sodium-Iodide Symporters
D002272:Carcinoembryonic Antigen; D007457:Iodine Radioisotopes; D011993:Recombinant Fusion Proteins; D027981:Symporters; D000099209:Sodium-Iodide Symporters