Oncolytic H-1 Parvovirus Shows Safety and Signs of Immunogenic Activity in a First Phase I/IIa Glioblastoma Trial
Karsten Geletneky, Jacek Hajda, Assia L Angelova, Barbara Leuchs, David Capper, Andreas J Bartsch, Jan-Oliver Neumann, Tilman Schöning, Johannes Hüsing, Birgit Beelte, Irina Kiprianova, Mandy Roscher, Rauf Bhat, Andreas von Deimling, Wolfgang Brück, Alexandra Just, Veronika Frehtman, Stephanie Löbhard, Elena Terletskaia-Ladwig, Jeremy Fry, Karin Jochims, Volker Daniel, Ottheinz Krebs, Michael Dahm, Bernard Huber, Andreas Unterberg, Jean Rommelaere, Karsten Geletneky, Jacek Hajda, Assia L Angelova, Barbara Leuchs, David Capper, Andreas J Bartsch, Jan-Oliver Neumann, Tilman Schöning, Johannes Hüsing, Birgit Beelte, Irina Kiprianova, Mandy Roscher, Rauf Bhat, Andreas von Deimling, Wolfgang Brück, Alexandra Just, Veronika Frehtman, Stephanie Löbhard, Elena Terletskaia-Ladwig, Jeremy Fry, Karin Jochims, Volker Daniel, Ottheinz Krebs, Michael Dahm, Bernard Huber, Andreas Unterberg, Jean Rommelaere
Abstract
Oncolytic virotherapy may be a means of improving the dismal prognosis of malignant brain tumors. The rat H-1 parvovirus (H-1PV) suppresses tumors in preclinical glioma models, through both direct oncolysis and stimulation of anticancer immune responses. This was the basis of ParvOryx01, the first phase I/IIa clinical trial of an oncolytic parvovirus in recurrent glioblastoma patients. H-1PV (escalating dose) was administered via intratumoral or intravenous injection. Tumors were resected 9 days after treatment, and virus was re-administered around the resection cavity. Primary endpoints were safety and tolerability, virus distribution, and maximum tolerated dose (MTD). Progression-free and overall survival and levels of viral and immunological markers in the tumor and peripheral blood were also investigated. H-1PV treatment was safe and well tolerated, and no MTD was reached. The virus could cross the blood-brain/tumor barrier and spread widely through the tumor. It showed favorable pharmacokinetics, induced antibody formation in a dose-dependent manner, and triggered specific T cell responses. Markers of virus replication, microglia/macrophage activation, and cytotoxic T cell infiltration were detected in infected tumors, suggesting that H-1PV may trigger an immunogenic stimulus. Median survival was extended in comparison with recent meta-analyses. Altogether, ParvOryx01 results provide an impetus for further H-1PV clinical development.
Keywords: clinical trial; glioblastoma; oncolytic parvovirus; tumor microenvironment.
Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
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References
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