An immunocompetent murine model for oncolysis with an armed and targeted measles virus.
An immunocompetent model is required to test therapeutic regimens for clinical trials with the oncolytic measles virus (MV). Toward developing this model, a retargeted MV that enters murine colon adenocarcinoma cells forming tumors in syngeneic C57BL/6 mice was generated. Since MV infection tends to be less efficient in murine than in human cells, the targeted virus was also armed with the prodrug convertase, purine nucleoside phosphorylase (PNP), and named MV-PNP-antiCEA. We have shown before that in cultured cells, infection with this virus activated the prodrug, 6-methylpurine-2'-deoxyriboside (MeP-dR), causing extensive cytotoxicity. When injected intratumorally (IT), MV-PNP-antiCEA inhibited subcutaneous tumor growth marginally, but subsequent administration of the prodrug enhanced the oncolytic effect. Systemic delivery of MV-PNP-antiCEA alone had no substantial oncolytic effects, but in combination with the prodrug it was therapeutic, revealing synergistic effects between virus and prodrug. Immunosuppression with cyclophosphamide (CPA) retarded the appearance of MV neutralizing antibodies and enhanced oncolytic efficacy: survival was 100%, with 9 out of 10 animals going into complete remission. This immunocompetent murine model facilitates the testing of therapeutic regimens for clinical trials.
Ungerechts
Guy
G
Molecular Medicine Program and Virology and Gene Therapy Track, Mayo Clinic College of Medicine, Rochester, Minnesota 55902, USA.
Springfeld
Christoph
C
Frenzke
Marie E
ME
Lampe
Johanna
J
Parker
William B
WB
Sorscher
Eric J
EJ
Cattaneo
Roberto
R
D000818:Animals; D024201:Bystander Effect; D002460:Cell Line; D002522:Chlorocebus aethiops; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D003520:Cyclophosphamide / Q000494:pharmacology; D004195:Disease Models, Animal; D018390:Gene Targeting; D015316:Genetic Therapy / Q000009:adverse effects; D007121:Immunocompetence / Q000276:immunology*; D007165:Immunosuppression Therapy; D008457:Measles / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008459:Measles virus / Q000187:drug effects / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011355:Prodrugs / Q000627:therapeutic use / Q000633:toxicity; D015996:Survival Rate
D011355:Prodrugs; D003520:Cyclophosphamide