TY - JOUR
T1 - Systemically delivered measles virus-infected mesenchymal stem cells can evade host immunity to inhibit liver cancer growth
AU - Ong, Hooi Tin
AU - Federspiel, Mark J.
AU - Guo, Chang M.
AU - Ooi, London Lucien
AU - Russell, Stephen J.
AU - Peng, Kah Whye
AU - Hui, Kam M.
N1 - Funding Information:
This work was supported by grants from the National Medical Research Council , Biomedical Research Council of Singapore , The Singapore Millennium Foundation and the SingHealth Foundation .
PY - 2013/11
Y1 - 2013/11
N2 - Background & Aims Although attenuated measles virus (MV) has demonstrated potent oncolytic activities towards human cancers, it has not yet been widely adopted into clinical practice. One of the major hurdles is the presence of pre-existing anti-MV immunity in the recipients. In this study, we have evaluated the combination of the potent oncolytic activity of the attenuated MV with the unique immunoprivileged and tumor-tropic biological properties of human bone marrow-derived mesenchymal stem cells (BM-hMSCs) to combat human hepatocellular carcinoma (HCC), orthotopically implanted in SCID mice, passively immunized with human neutralizing antibodies against MV as a preclinical model. Methods SCID mice were orthotopically implanted with patient-derived HCC tissues and established HCC cell lines. SCID mice were passively immunized with human neutralizing anti-measles antibodies. Bioluminescence and fluorescence imaging were employed to monitor the ability of systemically delivered MV-infected BM-hMSCs to infiltrate the implanted tumors and their effects on tumor growth. Results Systemically delivered MV-infected BM-hMSCs homed to the HCC tumors implanted orthotopically in the liver and it was evidenced that BM-hMSCs could transfer MV infectivity to HCC via heterofusion. Furthermore, therapy with MV-infected BM-hMSCs resulted in significant inhibition of tumor growth in both measles antibody-naïve and passively-immunized SCID mice. By contrast, when cell-free MV viruses were delivered systemically, antitumor activity was evident only in measles antibody-naïve SCID mice. Conclusions MV-infected BM-hMSCs cell delivery system provides a feasible strategy to elude the presence of immunity against MV in most of the potential cancer patients to be treated with the oncolytic MV viruses.
AB - Background & Aims Although attenuated measles virus (MV) has demonstrated potent oncolytic activities towards human cancers, it has not yet been widely adopted into clinical practice. One of the major hurdles is the presence of pre-existing anti-MV immunity in the recipients. In this study, we have evaluated the combination of the potent oncolytic activity of the attenuated MV with the unique immunoprivileged and tumor-tropic biological properties of human bone marrow-derived mesenchymal stem cells (BM-hMSCs) to combat human hepatocellular carcinoma (HCC), orthotopically implanted in SCID mice, passively immunized with human neutralizing antibodies against MV as a preclinical model. Methods SCID mice were orthotopically implanted with patient-derived HCC tissues and established HCC cell lines. SCID mice were passively immunized with human neutralizing anti-measles antibodies. Bioluminescence and fluorescence imaging were employed to monitor the ability of systemically delivered MV-infected BM-hMSCs to infiltrate the implanted tumors and their effects on tumor growth. Results Systemically delivered MV-infected BM-hMSCs homed to the HCC tumors implanted orthotopically in the liver and it was evidenced that BM-hMSCs could transfer MV infectivity to HCC via heterofusion. Furthermore, therapy with MV-infected BM-hMSCs resulted in significant inhibition of tumor growth in both measles antibody-naïve and passively-immunized SCID mice. By contrast, when cell-free MV viruses were delivered systemically, antitumor activity was evident only in measles antibody-naïve SCID mice. Conclusions MV-infected BM-hMSCs cell delivery system provides a feasible strategy to elude the presence of immunity against MV in most of the potential cancer patients to be treated with the oncolytic MV viruses.
KW - Hepatocellular carcinoma
KW - Human neutralizing antibody
KW - Mesenchymal stem cells as cell delivery vehicles
KW - Oncolytic measles virus
KW - Orthotopically implanted HCC tumor model
KW - Systemic virotherapy
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U2 - 10.1016/j.jhep.2013.07.010
DO - 10.1016/j.jhep.2013.07.010
M3 - Article
C2 - 23867315
AN - SCOPUS:84885953332
SN - 0168-8278
VL - 59
SP - 999
EP - 1006
JO - Journal of hepatology
JF - Journal of hepatology
IS - 5
ER -