TY - JOUR
T1 - Enhancing the oncolytic activity of CD133-targeted measles virus
T2 - Receptor extension or chimerism with vesicular stomatitis virus are most effective
AU - Kleinlützum, Dina
AU - Julia, Julia D.
AU - Muik, Alexander
AU - Hanschmann, Kay Martin
AU - Kays, Sarah Katharina
AU - Ayala-Breton, Camilo
AU - Peng, Kah Whye
AU - Mühlebach, Michael D.
AU - Abel, Tobias
AU - Buchholz, Christian J.
N1 - Funding Information:
The authors like to thank Tatjana Weidner, Lea Patasic, and Gundula Braun for excellent technical assistance as well as Christel Herold-Mende for providing the glioma cell NCH644. This work has been supported by a grant from the Deutsche Forschungsgemeinschaft to CB (BU 1301/3-1).
Publisher Copyright:
© 2017 Kleinlützum, Hanauer, Muik, Hanschmann, Kays, Ayala-Breton, Peng, Mühlebach, Abel and Buchholz.
PY - 2017/6/26
Y1 - 2017/6/26
N2 - Therapy resistance and tumor recurrence are often linked to a small refractory and highly tumorigenic subpopulation of neoplastic cells, known as cancer stem cells (CSCs). A putative marker of CSCs is CD133 (prominin-1). We have previously described a CD133-targeted oncolytic measles virus (MV-CD133) as a promising approach to specifically eliminate CD133-positive tumor cells. Selectivity was introduced at the level of cell entry by an engineered MV hemagglutinin (H). The H protein was blinded for its native receptors and displayed a CD133-specific single-chain antibody fragment (scFv) as targeting domain. Interestingly, MV-CD133 was more active in killing CD133-positive tumors than the unmodified MV-NSe despite being highly selective for its target cells. To further enhance the antitumoral activity of MV-CD133, we here pursued arming technologies, receptor extension, and chimeras between MV-CD133 and vesicular stomatitis virus (VSV). All newly generated viruses including VSV-CD133 were highly selective in eliminating CD133-positive cells. MV-CD46/CD133 killed in addition CD133-negative cells being positive for the MV receptors. In an orthotopic glioma model, MV-CD46/CD133 and MVSCD-CD133, which encodes the super cytosine deaminase, were most effective. Notably, VSV-CD133 caused fatal neurotoxicity in this tumor model. Use of CD133 as receptor could be excluded as being causative. In a subcutaneous tumor model of hepatocellular cancer, VSV-CD133 revealed the most potent oncolytic activity and also significantly prolonged survival of the mice when injected intravenously. Compared to MV-CD133, VSV-CD133 infected a more than 104-fold larger area of the tumor within the same time period. Our data not only suggest new concepts and approaches toward enhancing the oncolytic activity of CD133-targeted oncolytic viruses but also raise awareness about careful toxicity testing of novel virus types.
AB - Therapy resistance and tumor recurrence are often linked to a small refractory and highly tumorigenic subpopulation of neoplastic cells, known as cancer stem cells (CSCs). A putative marker of CSCs is CD133 (prominin-1). We have previously described a CD133-targeted oncolytic measles virus (MV-CD133) as a promising approach to specifically eliminate CD133-positive tumor cells. Selectivity was introduced at the level of cell entry by an engineered MV hemagglutinin (H). The H protein was blinded for its native receptors and displayed a CD133-specific single-chain antibody fragment (scFv) as targeting domain. Interestingly, MV-CD133 was more active in killing CD133-positive tumors than the unmodified MV-NSe despite being highly selective for its target cells. To further enhance the antitumoral activity of MV-CD133, we here pursued arming technologies, receptor extension, and chimeras between MV-CD133 and vesicular stomatitis virus (VSV). All newly generated viruses including VSV-CD133 were highly selective in eliminating CD133-positive cells. MV-CD46/CD133 killed in addition CD133-negative cells being positive for the MV receptors. In an orthotopic glioma model, MV-CD46/CD133 and MVSCD-CD133, which encodes the super cytosine deaminase, were most effective. Notably, VSV-CD133 caused fatal neurotoxicity in this tumor model. Use of CD133 as receptor could be excluded as being causative. In a subcutaneous tumor model of hepatocellular cancer, VSV-CD133 revealed the most potent oncolytic activity and also significantly prolonged survival of the mice when injected intravenously. Compared to MV-CD133, VSV-CD133 infected a more than 104-fold larger area of the tumor within the same time period. Our data not only suggest new concepts and approaches toward enhancing the oncolytic activity of CD133-targeted oncolytic viruses but also raise awareness about careful toxicity testing of novel virus types.
KW - Glioblastoma
KW - Hepatocellular carcinoma
KW - Prominin-1
KW - Tumorsphere
KW - Virotherapy
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U2 - 10.3389/fonc.2017.00127
DO - 10.3389/fonc.2017.00127
M3 - Article
AN - SCOPUS:85021229956
SN - 2234-943X
VL - 7
JO - Frontiers in Oncology
JF - Frontiers in Oncology
IS - JUN
M1 - 127
ER -