TY - JOUR
T1 - An immunocompetent murine model for oncolysis with an armed and targeted measles virus
AU - Ungerechts, Guy
AU - Springfeld, Christoph
AU - Frenzke, Marie E.
AU - Lampe, Johanna
AU - Parker, William B.
AU - Sorscher, Eric J.
AU - Cattaneo, Roberto
N1 - Funding Information:
Mayo and Siebens Foundations and a grant (UN 254 1-1) from the Deutsche Forschungsgemeinschaft (German Research Foundation) helped support this study. We thank Steve Russell and Richard Vile for comments regarding this manuscript, Jeong Hong for providing the PNP-antibody, and Nathan Foster for his statistical analyses. Conflict-of-interest disclosure: W.B.P. and E.J.S. have a significant equity position in PNP Therapeutics.
PY - 2007/11
Y1 - 2007/11
N2 - 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.
AB - 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.
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U2 - 10.1038/sj.mt.6300291
DO - 10.1038/sj.mt.6300291
M3 - Article
C2 - 17712331
AN - SCOPUS:35549009347
SN - 1525-0016
VL - 15
SP - 1991
EP - 1997
JO - Molecular Therapy
JF - Molecular Therapy
IS - 11
ER -