The use of a tropism-modified measles virus in folate receptor-targeted virotherapy of ovarian cancer.
OBJECTIVE
Attenuated measles viruses are promising experimental anticancer agents currently being evaluated in a phase I dose escalation trial for ovarian cancer patients. Virus attachment, entry, and subsequent intercellular fusion between infected and uninfected neighboring cells are mediated via the two measles receptors (CD46 and SLAM). To minimize potential toxicity due to measles virus-associated immunosuppression and infection of nontarget tissues, we sought to develop an ovarian cancer exclusive fully retargeted measles virus.


RESULTS
Interactions of measles virus with its natural receptors were ablated, and a single-chain antibody (scFv) specific for alpha-folate receptor (FRalpha), a target overexpressed on 90% of nonmucinous ovarian cancer, was genetically engineered on the viral attachment protein (MV-alphaFR). Specificity of virus tropism was tested on tumor and normal cells. Biodistribution of measles virus infection was evaluated in measles-susceptible CD46 transgenic mice, whereas antitumor activity was monitored noninvasively by bioluminescence imaging in xenograft models. Tropism and fusogenic activity of MV-alphaFR was redirected exclusively to FRalpha without compromise to virus infectivity. In contrast to the parental virus, MV-alphaFR has no background infectivity on normal human cells. The antitumor activity of MV-alphaFR, as assessed by tumor volume reduction and overall survival increase, was equal to the parental virus in two models of human ovarian cancer (s.c. and i.p.).


CONCLUSIONS
A FR-exclusive ovarian cancer targeted oncolytic virus was generated and shown to be therapeutically effective, thus introducing a new modality for FR targeting and a candidate measles virus for clinical testing.
Hasegawa
Kosei
K
Molecular Medicine Program, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Nakamura
Takafumi
T
Harvey
Mary
M
Ikeda
Yasuhiro
Y
Oberg
Ann
A
Figini
Mariangela
M
Canevari
Silvana
S
Hartmann
Lynn C
LC
Peng
Kah-Whye
KW
D019496:Cancer Vaccines; D002352:Carrier Proteins / Q000502:physiology*; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005822:Genetic Vectors; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008214:Lymphocytes / Q000276:immunology*; D008459:Measles virus; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000821:virology; D011956:Receptors, Cell Surface / Q000502:physiology*; D012016:Reference Values; D014613:Vaccines, Attenuated; D014765:Viral Vaccines
D019496:Cancer Vaccines; D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D011956:Receptors, Cell Surface; D014613:Vaccines, Attenuated; D014765:Viral Vaccines