Mesenchymal stem cell carriers protect oncolytic measles viruses from antibody neutralization in an orthotopic ovarian cancer therapy model.
OBJECTIVE
Preexisting antiviral antibodies in cancer patients can quickly neutralize oncolytic measles virus (MV) and decrease its antitumor potency. In contrast to "naked" viruses, cell-associated viruses are protected from antibody neutralization. Hence, we hypothesized that measles virotherapy of ovarian cancer in measles-immune mice might be superior if MV-infected mesenchymal stem cell (MSC) carriers are used.


METHODS
Antimeasles antibodies titers in ovarian cancer patients were determined. The protection of MV by MSC from antimeasles antibodies, the in vivo biodistribution profiles, and tumor infiltration capability of MSC were determined. Measles-naïve or immune tumor-bearing mice were treated with naked virus or MSC-associated virus and mice survivals were compared.


RESULTS
MSC transferred MV infection to target cells via cell-to-cell heterofusion and induced syncytia formation in the presence of high titers of antimeasles antibody, at levels that completely inactivated naked virus. Athymic mice bearing i.p. human SKOV3ip.1 ovarian tumor xenografts passively immunized with measles-immune human serum were treated with saline, naked MV, or MV-infected MSC. Bioluminescent and fluorescent imaging data indicated that i.p. administered MSC localized to peritoneal tumors, infiltrated into the tumor parenchyma, and transferred virus infection to tumors in measles naïve and passively immunized mice. Survival of the measles-immune mice was significantly enhanced by treatment with MV-infected MSC. In contrast, survivals of passively immunized mice were not prolonged by treatment with naked virus or uninfected MSC.


CONCLUSIONS
MSC should be used as carriers of MV for intraperitoneal virotherapy in measles-immune ovarian cancer patients.
Mader
Emily K
EK
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
Maeyama
Yoshihiro
Y
Lin
Yi
Y
Butler
Greg W
GW
Russell
Holly M
HM
Galanis
Evanthia
E
Russell
Stephen J
SJ
Dietz
Allan B
AB
Peng
Kah-Whye
KW
D000818:Animals; D019496:Cancer Vaccines; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D008459:Measles virus / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000628:therapy*; D014709:Vero Cells
D019496:Cancer Vaccines; D007074:Immunoglobulin G