Enhancing the oncolytic activity of CD133-targeted measles virus: Receptor extension or chimerism with vesicular stomatitis virus are most effective

Dina Kleinlützum, Julia D. Julia, Alexander Muik, Kay Martin Hanschmann, Sarah Katharina Kays, Camilo Ayala-Breton, Kah Whye Peng, Michael D. Mühlebach, Tobias Abel, Christian J. Buchholz

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number127
JournalFrontiers in Oncology
Volume7
Issue numberJUN
DOIs
StatePublished - Jun 26 2017

Keywords

  • Glioblastoma
  • Hepatocellular carcinoma
  • Prominin-1
  • Tumorsphere
  • Virotherapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Kleinlützum, D., Julia, J. D., Muik, A., Hanschmann, K. M., Kays, S. K., Ayala-Breton, C., Peng, K. W., Mühlebach, M. D., Abel, T., & Buchholz, C. J. (2017). Enhancing the oncolytic activity of CD133-targeted measles virus: Receptor extension or chimerism with vesicular stomatitis virus are most effective. Frontiers in Oncology, 7(JUN), [127]. https://doi.org/10.3389/fonc.2017.00127