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.
Highlights
Despite considerable progress in cancer therapy, relapse and dissemination of tumor cells remain a frequent therapeutic outcome, which is more and more ascribed to an insufficient targeting and killing of a small population of tumor cells with stem-cell like properties [1]
We show that in glioma, measles virus (MV) using CD133 and CD46 as receptors are promising, while for hepatocellular cancer (HCC) or other carcinomas not involving the central nervous system, vesicular stomatitis virus (VSV) targeted to CD133 appears to be the best choice
The GFP reporter gene was exchanged against the suicide gene super cytosine deaminase (SCD), which converts the prodrug 5-fluorocytosine (5-FC) into 5-fluorouracil (5-FU) resulting in MVSCD-CD133 [36]
Summary
Despite considerable progress in cancer therapy, relapse and dissemination of tumor cells remain a frequent therapeutic outcome, which is more and more ascribed to an insufficient targeting and killing of a small population of tumor cells with stem-cell like properties [1]. Such cancer stem cells (CSCs) were initially detected in tumors of hematopoietic origin demonstrating that only a small fraction of cells in the tumor mass is capable of forming metastasis and new tumors [2]. Since further recent articles came to the same conclusion for glioma [7,8,9] as for hepatocellular cancer (HCC) [10, 11], targeting of CD133 remains an attractive therapeutic concept for these cancer entities and possibly for others
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