Abstract
Tumor-initiating cells (TIC) are critical yet evasive targets for the development of more effective antitumoral strategies. The cell surface marker CD133 is frequently used to identify TICs of various tumor entities, including hepatocellular cancer and glioblastoma. Here, we describe oncolytic measles viruses (MV) retargeted to CD133. The viruses, termed MV-141.7 and MV-AC133, infected and selectively lysed CD133(+) tumor cells. Both viruses exerted strong antitumoral effects on human hepatocellular carcinoma growing subcutaneously or multifocally in the peritoneal cavity of nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Notably, the CD133-targeted viruses were more effective in prolonging survival than the parental MV-NSe, which is currently assessed as oncolytic agent in clinical trials. Interestingly, target receptor overexpression or increased spreading kinetics through tumor cells were excluded as being causative for the enhanced oncolytic activity of CD133-targeted viruses. MV-141.7 was also effective in mouse models of orthotopic glioma tumor spheres and primary colon cancer. Our results indicate that CD133-targeted measles viruses selectively eliminate CD133(+) cells from tumor tissue, offering a key tool for research in tumor biology and cancer therapy.
Highlights
Tumor-initiating cells (TICs) form an attractive target for novel antitumoral strategies as they differentiate into cancer cells forming the tumor mass and were shown to be resistant toward conventional therapies, such as radio- and chemotherapy
To generate CD133-specific measles viruses, scFv-reading frames cloned from the hybridoma cell lines AC141.7 or AC133 were fused to that of the measles virus H protein mutant deficient in receptor recognition
Western blot analysis of virus stocks confirmed that the anti-CD133 scFv displaying H proteins were properly expressed and incorporated into virus particles (Fig. 1A)
Summary
Tumor-initiating cells (TICs) form an attractive target for novel antitumoral strategies as they differentiate into cancer cells forming the tumor mass and were shown to be resistant toward conventional therapies, such as radio- and chemotherapy (for review see ref. 1). Tumor-initiating cells (TICs) form an attractive target for novel antitumoral strategies as they differentiate into cancer cells forming the tumor mass and were shown to be resistant toward conventional therapies, such as radio- and chemotherapy CD133 is mainly expressed on stem cells of the hematopoietic and the endothelial system with a yet unknown physiologic function [2]. Authors' Affiliations: 1Medical Biotechnology and Gene Therapy and 2Oncolytic Measles Viruses and Vectored Vaccines, Paul-Ehrlich-Institut, Langen; 3Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ); 4Division of Neurosurgical Research, Department of Neurosurgery, University of Heidelberg, Heidelberg; 5Miltenyi Biotec GmbH, Bergisch-Gladbach; and 6Department of Internal Medicine I, Medical University Hospital, Tuebingen, Germany
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