Artikel
Multiple intravenous injections of oncolytic Parvovirus H-1 lead to complete tumor regression of rat and human glioma xenografts similar to intratumoral therapy
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Autoren
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Karsten Geletneky
- Neurochirurgische Klinik Heidelberg, Germany; Abteilung Tumorvirologie (F010), Deutsches Krebsforschungszentrum Heidelberg, Germany
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Irina KiprianovaI
- Abteilung Tumorvirologie (F010), Deutsches Krebsforschungszentrum Heidelberg, Germany; Cancer Virotherapy Unit (U 701), Institut National de la Santé et de la Recherche Médicale (INSERM) Heidelberg, Germany
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Ali Ayache
- Abteilung Tumorvirologie (F010), Deutsches Krebsforschungszentrum Heidelberg, Germany
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Regina Koch
- Department of Radiology, The Ohio State University, Columbus, USA
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Soner Muhcu
- Neurochirurgische Klinik Heidelberg, Germany
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Clemens Sommer
- Neuropathologie Mainz, Germany
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Nadja Thomas
- Abteilung Tumorvirologie (F010), Deutsches Krebsforschungszentrum Heidelberg, Germany
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Andreas Unterberg
- Neurochirurgische Klinik Heidelberg, Germany
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Jean Rommelaere
- Abteilung Tumorvirologie (F010), Deutsches Krebsforschungszentrum Heidelberg, Germany
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Jörg R. Schlehofer
- Abteilung Tumorvirologie (F010), Deutsches Krebsforschungszentrum Heidelberg, Germany
| Veröffentlicht: | 16. September 2010 |
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Gliederung
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Objective: The treatment of malignant gliomas remains an unsolved problem requiring alternative treatment modalities. The use of oncolytic viruses that specifically target and destroy tumor cells is under investigation also for glioblastomas. One candidate virus for glioma therapy is the rodent parvovirus H-1 (H-1PV) which is completely apathogenic in humans. H-1PV has been shown to induce oncolysis in gliomas after intratumoral injection. The goal of this study was to compare the therapeutic effect of systemic and local H-1PV therapy.
Methods: H-1PV-based virotherapy of glioma was tested in rat (RG-2) and human (U87) glioma xenografts in immunocompetent and immunodeficient rats. Initially, large orthotopic gliomas were infected by single stereotactic intratumoral injection. Subsequently, based on findings that H-1PV is able to cross the blood brain barrier, tumor bearing animals were treated with multiple intravenous H-1PV infections. The oncolytic effect was monitored by MRI, animal survival and proven by histology. Virus distribution and replication were determined in brain and organs.
Results: In immunocompetent rats bearing RG-2-derived tumors, multiple (n=8) intravenous applications of H-1PV, as well as a single stereotactic intratumoral injection of the virus were sufficient to achieve complete remission of advanced and even symptomatic intracranial gliomas in 67% of treated animals. Both treatments were well tolerated and no damage of normal brain tissue or other organs was observed. H-1PV therapy resulted in significantly improved survival (Kaplan-Meier analysis) in both, the rat and human glioma models (p<0.001). Virus replication could be shown in infected tumor cells, but not in normal brain tissue, indicating a contribution of secondary infection by progeny virus to the efficiency of oncolysis. H-1PV DNA could be detected in tumors and transiently in adjacent or remote normal brain tissue and in non-cerebral tissues.
Conclusions: H-1PV also possesses high oncolytic activity in malignant gliomas after intravenous injection. The results presented here are the basis for a planned phase I/IIa trial of H-1PV in glioblastoma patients. The possibility for local and systemical glioma virotherapy is a unique feature of H-1PV and offers new treatment options for this tumor entity.
