Spezifische Eliminierung von Tumorstammzellen mit Hilfe von onkolytischen Viren
Zellbiologie
Zusammenfassung der Projektergebnisse
Tumors do not consist of homogenous cell populations but contain cancer stem cells which respond poorly to chemotherapy and radiotherapy and are considered to be responsible for metastatic tumors. Scientists have therefore stepped up their efforts to find ways of identifying and eliminating these “tumour-initiating cells”. The cell surface protein CD133 is a putative marker for such cancer stem cells. In this project we have modified an attenuated and thus innocuous measles virus (MV) for the targeted attack on cancer stem cells. The modified virus requires the surface protein CD133 as receptor for penetration into the cell. We were able to prove that the modified virus infects only CD133-positive tumor cells even when these are cultivated in close contact with CD133-negative cells. The viruses exhibited pronounced anti-tumoral activity in mouse models reflecting glioma, colon carcinoma, and liver cancer. In all animal models tested – the tumor growth was substantially reduced or even entirely suppressed. However, there was also evidence for the regeneration of CD133-positive from CD133-negative cells. Surprisingly, the effectiveness of the modified oncolytic measles virus was more pronounced than that of an unmodified oncolytic measles virus that is investigated in clinical trials. The CD133-specific antibody fragment presented on the virus surface could be excluded as being causative for this effect. Possibly, a subfraction of cells responsible for maintenance and dissemination of the tumor is eliminated by the virus. Importantly, hematopoietic stem cells were not attacked by the oncolytic measles virus. To further enhance the anti-tumoral activity of CD133-targeted MV we have furthermore pursued arming technologies, receptor extension and chimeras between MV-CD133 and vesicular stomatitis virus (VSV). The data show that all oncolytic viruses (OVs) selectively infected and lysed their target cells. In terms of anti-tumoral activity, MV-CD133-CD46, which can use both, CD46 and CD133, as entry receptor, and VSV-CD133 performed best in vitro and in vivo. Further, while immunostaining revealed replicating virus in all tumors of all treatment groups, the numbers and sizes of infectious centers in VSV-CD133 treated mice were up to 3-log steps higher than within MV-treated tumors. Unexpectedly, however, VSV- CD133 caused neurotoxicity in the orthotopic glioma model. Use of CD133 as receptor could be excluded as being causative. Our data reveal new concepts and approaches towards enhancing the oncolytic activity of tumor-targeted OVs but also raise awareness about careful toxicity testing of novel OV types. A press release was published with publication of our manuscript in Cancer Research. This press release was taken up by many media including daily press with such widely distributed newspapers as “Bild” and “Bild am Sonntag” and resulted even in a title page header in “Bild”.
Projektbezogene Publikationen (Auswahl)
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2013. Enhanced tumor therapy by tumor stem cell targeted oncolytic viruses. WO2012117116 A3
Buchholz CJ, Bach P, Abel T
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2013. Specific elimination of CD133+ tumor cells with targeted oncolytic measles virus. Cancer Research 73: 865-74
Bach P, Abel T, Hoffmann C, Gal Z, Braun G, Voelker I, Ball CR, Johnston IC, Lauer UM, Herold-Mende C, Mühlebach MD, Glimm H, Buchholz CJ
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2016. Enhanced lysis by bispecific oncolytic measles viruses simultaneously using HER2/neu or EpCAM as target receptors. Molecular Therapy Oncolytics 3:16003
Hanauer JR, Gottschlich L, Riehl D, Rusch T, Koch V, Friedrich K, Hutzler S, Prüfer S, Friedel T, Hanschmann KM, Münch RC, Jost C, Plückthun A, Cichutek K, Buchholz CJ, Mühlebach MD
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Enhancing the Oncolytic Activity of CD133-Targeted Measles Virus: Receptor Extension or Chimerism with Vesicular Stomatitis Virus Are Most Effective. Frontiers in Oncology, 26 June 2017
Kleinlützum D, Hanauer JDS, Muik A, Hanschmann KM, Kays SK, Ayala-Breton C, Peng KW, Mühlebach MD, Abel T, Buchholz CJ
