Enhancing the Oncolytic Activity of CD133-Targeted Measles Virus: Receptor Extension or Chimerism with Vesicular Stomatitis Virus Are Most Effective

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.

Recent advances in vesicular stomatitis virus-based oncolytic virotherapy: a 5-year update

“…More recently, a similar approach was used to retarget replication-competent chimeric VSV-FH to cancer cells, especially ovarian cancer cells, expressing HER-2/neu receptor [42]. In another study, VSV encoding CD133-targeted MV-H and the MV-F was generated and successfully targeted cancer cells expressing a putative marker of cancer stem cells CD133 in a subcutaneous hepatocellular carcinoma (HCC) xenograft model [43]. As MV also infects nectin4-positive airway epithelial cells, a modified VSV-FH recombinant was generated with H mutations that disrupts binding to nectin4, which were expected to improve the virus oncoselectivity by limiting its binding only to CD46.…”

In vivo antitumor activity by dual stromal and tumor-targeted oncolytic measles viruses

“…Second, they emphasize the importance of the tumor microenvironment on tumor progression, and validate the tumor stroma as a target for oncolytic virotherapies in general, and oncolytic MVs in particular. Prior studies have characterized fully retargeted MVs directed against multiple receptors, such as the epithelial receptors Her-2/ neu and EpCAM [46], or against CD46 and CD133 [47], among other retargeted oncolytic MVs. Although these strategies enhance and potentiate tumor targeting, they do not address the important question of stromal targeting by MV vectors.…”

DCLK1 Expression in Colorectal Polyps Increases with the Severity of Dysplasia

“…For the association of CD133 with CRC treatment, several studies have reported that CD133-positive CRC might be resistant to chemotherapy or chemoradiotherapy (41)(42)(43). Moreover, CD133-targeted oncolytic measles virus has been shown to specifically eliminate CD133-positive tumor cells (glioblastoma and hepatocellular carcinoma) in a murine model (44); however, fatal neurotoxicity was developed in this model. Based on these studies, DCLK1 seems to be the most promising target for CRC treatment, at present.…”