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2. H-1 Parvovirus-Induced Oncolysis and Tumor Microenvironment Immune Modulation in a Novel Heterotypic Spheroid Model of Cutaneous T-Cell Lymphoma.

Author

Angelova, Assia, Barf, Milena, Just, Alexandra, Leuchs, Barbara, Rommelaere, Jean, and Ungerechts, Guy

Subjects
ADENOSINE triphosphate metabolism, ONCOLYTIC virotherapy, NON-Hodgkin's lymphoma, RESEARCH funding, PILOT projects, CUTANEOUS T-cell lymphoma, RATS, CELL lines, GENE expression, ANIMAL experimentation, CELL survival, PARVOVIRUS diseases, CELL receptors
Abstract

Simple Summary: Cutaneous T-cell lymphoma (CTCL) is a rare type of T-lymphocyte malignancy strongly calling for novel therapies. Virotherapy by means of oncolytic viruses that are able to kill cancer cells, while sparing healthy cells, is a promising innovative form of anticancer immunotherapy. The aim of this study was to investigate the potential of an oncolytic parvovirus, H-1PV, to induce selective killing (oncolysis) of CTCL cells and suppress the growth of CTCL spheroids. We demonstrated that H-1PV treatment led to oncolysis in tumor, but not in control normal cells. Oncolysis ensued despite pro-survival protein overexpression and was associated with the release of danger-signaling molecules. In heterotypic CTCL spheroids, H-1PV induced spheroid growth suppression and, upon co-culturing with peripheral blood mononuclear cells, spheroid infiltration with immune cells. In summary, we gathered the first preclinical data showing that H-1PV holds significant potential to become a novel viroimmunotherapeutic agent against CTCL. The rat protoparvovirus H-1 (H-1PV) is an oncolytic virus known for its anticancer properties in laboratory models of various human tumors, including non-Hodgkin lymphomas (NHL) of B-cell origin. However, H-1PV therapeutic potential against hematological malignancies of T-cell origin remains underexplored. The aim of the present study was to conduct a pilot preclinical investigation of H-1PV-mediated oncolytic effects in cutaneous T-cell lymphoma (CTCL), a type of NHL that is urgently calling for innovative therapies. We demonstrated H-1PV productive infection and induction of oncolysis in both classically grown CTCL suspension cultures and in a novel, in vivo-relevant, heterotypic spheroid model, but not in healthy donor controls, including peripheral blood mononuclear cells (PBMCs). H-1PV-mediated oncolysis of CTCL cells was not prevented by Bcl-2 overexpression and was accompanied by increased extracellular ATP release. In CTCL spheroid co-cultures with PBMCs, increased spheroid infiltration with immune cells was detected upon co-culture treatment with the virus. In conclusion, our preclinical data show that H-1PV may hold significant potential as an ingenious viroimmunotherapeutic drug candidate against CTCL. [ABSTRACT FROM AUTHOR]

Published
2024
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5. Supplementary Figure 1 from Phase 2 Trial of Oncolytic H-1 Parvovirus Therapy Shows Safety and Signs of Immune System Activation in Patients With Metastatic Pancreatic Ductal Adenocarcinoma

Author

Hajda, Jacek, primary, Leuchs, Barbara, primary, Angelova, Assia L., primary, Frehtman, Veronika, primary, Rommelaere, Jean, primary, Mertens, Mieke, primary, Pilz, Maximilian, primary, Kieser, Meinhard, primary, Krebs, Ottheinz, primary, Dahm, Michael, primary, Huber, Bernard, primary, Engeland, Christine E., primary, Mavratzas, Athanasios, primary, Hohmann, Nicolas, primary, Schreiber, Jutta, primary, Jäger, Dirk, primary, Halama, Niels, primary, Sedlaczek, Oliver, primary, Gaida, Matthias M., primary, Daniel, Volker, primary, Springfeld, Christoph, primary, and Ungerechts, Guy, primary

Published
2023
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6. Supplementary Figure 2 from Phase 2 Trial of Oncolytic H-1 Parvovirus Therapy Shows Safety and Signs of Immune System Activation in Patients With Metastatic Pancreatic Ductal Adenocarcinoma

Author

Hajda, Jacek, primary, Leuchs, Barbara, primary, Angelova, Assia L., primary, Frehtman, Veronika, primary, Rommelaere, Jean, primary, Mertens, Mieke, primary, Pilz, Maximilian, primary, Kieser, Meinhard, primary, Krebs, Ottheinz, primary, Dahm, Michael, primary, Huber, Bernard, primary, Engeland, Christine E., primary, Mavratzas, Athanasios, primary, Hohmann, Nicolas, primary, Schreiber, Jutta, primary, Jäger, Dirk, primary, Halama, Niels, primary, Sedlaczek, Oliver, primary, Gaida, Matthias M., primary, Daniel, Volker, primary, Springfeld, Christoph, primary, and Ungerechts, Guy, primary

Published
2023
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7. Supplementary Figure 4 from Phase 2 Trial of Oncolytic H-1 Parvovirus Therapy Shows Safety and Signs of Immune System Activation in Patients With Metastatic Pancreatic Ductal Adenocarcinoma

Author

Hajda, Jacek, primary, Leuchs, Barbara, primary, Angelova, Assia L., primary, Frehtman, Veronika, primary, Rommelaere, Jean, primary, Mertens, Mieke, primary, Pilz, Maximilian, primary, Kieser, Meinhard, primary, Krebs, Ottheinz, primary, Dahm, Michael, primary, Huber, Bernard, primary, Engeland, Christine E., primary, Mavratzas, Athanasios, primary, Hohmann, Nicolas, primary, Schreiber, Jutta, primary, Jäger, Dirk, primary, Halama, Niels, primary, Sedlaczek, Oliver, primary, Gaida, Matthias M., primary, Daniel, Volker, primary, Springfeld, Christoph, primary, and Ungerechts, Guy, primary

Published
2023
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8. Supplementary Table 1 from Phase 2 Trial of Oncolytic H-1 Parvovirus Therapy Shows Safety and Signs of Immune System Activation in Patients With Metastatic Pancreatic Ductal Adenocarcinoma

Author

Hajda, Jacek, primary, Leuchs, Barbara, primary, Angelova, Assia L., primary, Frehtman, Veronika, primary, Rommelaere, Jean, primary, Mertens, Mieke, primary, Pilz, Maximilian, primary, Kieser, Meinhard, primary, Krebs, Ottheinz, primary, Dahm, Michael, primary, Huber, Bernard, primary, Engeland, Christine E., primary, Mavratzas, Athanasios, primary, Hohmann, Nicolas, primary, Schreiber, Jutta, primary, Jäger, Dirk, primary, Halama, Niels, primary, Sedlaczek, Oliver, primary, Gaida, Matthias M., primary, Daniel, Volker, primary, Springfeld, Christoph, primary, and Ungerechts, Guy, primary

Published
2023
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9. Supplementary Table 4 from Phase 2 Trial of Oncolytic H-1 Parvovirus Therapy Shows Safety and Signs of Immune System Activation in Patients With Metastatic Pancreatic Ductal Adenocarcinoma

Author

Hajda, Jacek, primary, Leuchs, Barbara, primary, Angelova, Assia L., primary, Frehtman, Veronika, primary, Rommelaere, Jean, primary, Mertens, Mieke, primary, Pilz, Maximilian, primary, Kieser, Meinhard, primary, Krebs, Ottheinz, primary, Dahm, Michael, primary, Huber, Bernard, primary, Engeland, Christine E., primary, Mavratzas, Athanasios, primary, Hohmann, Nicolas, primary, Schreiber, Jutta, primary, Jäger, Dirk, primary, Halama, Niels, primary, Sedlaczek, Oliver, primary, Gaida, Matthias M., primary, Daniel, Volker, primary, Springfeld, Christoph, primary, and Ungerechts, Guy, primary

Published
2023
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10. Supplementary Figure 3 from Phase 2 Trial of Oncolytic H-1 Parvovirus Therapy Shows Safety and Signs of Immune System Activation in Patients With Metastatic Pancreatic Ductal Adenocarcinoma

Author

Hajda, Jacek, primary, Leuchs, Barbara, primary, Angelova, Assia L., primary, Frehtman, Veronika, primary, Rommelaere, Jean, primary, Mertens, Mieke, primary, Pilz, Maximilian, primary, Kieser, Meinhard, primary, Krebs, Ottheinz, primary, Dahm, Michael, primary, Huber, Bernard, primary, Engeland, Christine E., primary, Mavratzas, Athanasios, primary, Hohmann, Nicolas, primary, Schreiber, Jutta, primary, Jäger, Dirk, primary, Halama, Niels, primary, Sedlaczek, Oliver, primary, Gaida, Matthias M., primary, Daniel, Volker, primary, Springfeld, Christoph, primary, and Ungerechts, Guy, primary

Published
2023
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12. Supplementary Table 2 from Phase 2 Trial of Oncolytic H-1 Parvovirus Therapy Shows Safety and Signs of Immune System Activation in Patients With Metastatic Pancreatic Ductal Adenocarcinoma

Author

Hajda, Jacek, primary, Leuchs, Barbara, primary, Angelova, Assia L., primary, Frehtman, Veronika, primary, Rommelaere, Jean, primary, Mertens, Mieke, primary, Pilz, Maximilian, primary, Kieser, Meinhard, primary, Krebs, Ottheinz, primary, Dahm, Michael, primary, Huber, Bernard, primary, Engeland, Christine E., primary, Mavratzas, Athanasios, primary, Hohmann, Nicolas, primary, Schreiber, Jutta, primary, Jäger, Dirk, primary, Halama, Niels, primary, Sedlaczek, Oliver, primary, Gaida, Matthias M., primary, Daniel, Volker, primary, Springfeld, Christoph, primary, and Ungerechts, Guy, primary

Published
2023
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13. Supplementary Table 3 from Phase 2 Trial of Oncolytic H-1 Parvovirus Therapy Shows Safety and Signs of Immune System Activation in Patients With Metastatic Pancreatic Ductal Adenocarcinoma

Author

Hajda, Jacek, primary, Leuchs, Barbara, primary, Angelova, Assia L., primary, Frehtman, Veronika, primary, Rommelaere, Jean, primary, Mertens, Mieke, primary, Pilz, Maximilian, primary, Kieser, Meinhard, primary, Krebs, Ottheinz, primary, Dahm, Michael, primary, Huber, Bernard, primary, Engeland, Christine E., primary, Mavratzas, Athanasios, primary, Hohmann, Nicolas, primary, Schreiber, Jutta, primary, Jäger, Dirk, primary, Halama, Niels, primary, Sedlaczek, Oliver, primary, Gaida, Matthias M., primary, Daniel, Volker, primary, Springfeld, Christoph, primary, and Ungerechts, Guy, primary

Published
2023
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17. THER-01. Precision brain tumor therapy by AAV-mediated oncogene editing

Author

von Soosten, Laura, primary, Haar, Janina, additional, Frehtman, Veronika, additional, Holderbach, Stefan, additional, Belzen, Julius Upmeier zu, additional, Jendrusch, Michael, additional, Okonechnikov, Konstantin, additional, Pfister, Stefan M, additional, Grimm, Dirk, additional, Leuchs, Barbara, additional, Jones, David, additional, Kutscher, Lena M, additional, and Zuckermann, Marc, additional

Published
2022
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18. Temporal multi-omics identifies LRG1 as a vascular niche instructor of metastasis

Author

Singhal, Mahak, primary, Gengenbacher, Nicolas, additional, Abdul Pari, Ashik Ahmed, additional, Kamiyama, Miki, additional, Hai, Ling, additional, Kuhn, Bianca J., additional, Kallenberg, David M., additional, Kulkarni, Shubhada R., additional, Camilli, Carlotta, additional, Preuß, Stephanie F., additional, Leuchs, Barbara, additional, Mogler, Carolin, additional, Espinet, Elisa, additional, Besemfelder, Eva, additional, Heide, Danijela, additional, Heikenwalder, Mathias, additional, Sprick, Martin R., additional, Trumpp, Andreas, additional, Krijgsveld, Jeroen, additional, Schlesner, Matthias, additional, Hu, Junhao, additional, Moss, Stephen E., additional, Greenwood, John, additional, and Augustin, Hellmut G., additional

Published
2021
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19. Phase 2 Trial of Oncolytic H-1 Parvovirus Therapy Shows Safety and Signs of Immune System Activation in Patients With Metastatic Pancreatic Ductal Adenocarcinoma

Author

Hajda, Jacek, primary, Leuchs, Barbara, additional, Angelova, Assia L., additional, Frehtman, Veronika, additional, Rommelaere, Jean, additional, Mertens, Mieke, additional, Pilz, Maximilian, additional, Kieser, Meinhard, additional, Krebs, Ottheinz, additional, Dahm, Michael, additional, Huber, Bernard, additional, Engeland, Christine E., additional, Mavratzas, Athanasios, additional, Hohmann, Nicolas, additional, Schreiber, Jutta, additional, Jäger, Dirk, additional, Halama, Niels, additional, Sedlaczek, Oliver, additional, Gaida, Matthias M., additional, Daniel, Volker, additional, Springfeld, Christoph, additional, and Ungerechts, Guy, additional

Published
2021
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21. Human Retrotransposons and the Global Shutdown of Homeostatic Innate Immunity by Oncolytic Parvovirus H-1PV in Pancreatic Cancer

Author

Neulinger-Muñoz, Matthias, primary, Schaack, Dominik, additional, Grekova, Svetlana P., additional, Bauer, Andrea S., additional, Giese, Thomas, additional, Salg, Gabriel A., additional, Espinet, Elisa, additional, Leuchs, Barbara, additional, Heller, Anette, additional, Nüesch, Jürg P. F., additional, Schenk, Miriam, additional, Volkmar, Michael, additional, and Giese, Nathalia A., additional

Published
2021
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25. TSC22D4 is a molecular output of hepatic wasting metabolism

Author

Jones, Allan, Friedrich, Kilian, Rohm, Maria, Schäfer, Michaela, Algire, Carolyn, Kulozik, Philipp, Seibert, Oksana, Müller-Decker, Karin, Sijmonsma, Tjeerd, Strzoda, Daniela, Sticht, Carsten, Gretz, Norbert, Dallinga-Thie, Geesje M., Leuchs, Barbara, Kögl, Manfred, Stremmel, Wolfgang, Diaz, Mauricio Berriel, and Herzig, Stephan

Published
2013
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30. Phase I/IIa study of intratumoral/intracerebral or intravenous/intracerebral administration of Parvovirus H-1 (ParvOryx) in patients with progressive primary or recurrent glioblastoma multiforme: ParvOryx01 protocol

Author

Geletneky Karsten, Huesing Johannes, Rommelaere Jean, Schlehofer Joerg R, Leuchs Barbara, Dahm Michael, Krebs Ottheinz, von Knebel Doeberitz Magnus, Huber Bernard, and Hajda Jacek

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background The treatment of patients with malignant brain tumors remains a major oncological problem. The median survival of patients with glioblastoma multiforme (GBM), the most malignant type, is only 15 months after initial diagnosis and even less after tumor recurrence. Improvements of standard treatment including surgery and radio-chemotherapy have not lead to major improvements. Therefore, alternative therapeutics such as oncolytic viruses that specifically target and destroy cancer cells are under investigation. Preclinical data of oncolytic parvovirus H-1 (H-1PV) infection of glioma cells demonstrated strong cytotoxic and oncosuppressing effects, leading to a phase I/IIa trial of H-1PV in patients with recurrent GBM (ParvOryx01). ParvOryx01 is the first trial with a replication competent oncolytic virus in Germany. Methods ParvOryx01 is an open, non-controlled, two groups, intra-group dose escalation, single center, phase I/IIa trial. 18 patients with recurrent GBM will be treated in 2 groups of 9 patients each. Treatment group 1 will first receive H-1PV by intratumoral injection and second by administration into the walls of the tumor cavity during tumor resection. In treatment group 2 the virus will initially be injected intravenously and afterwards, identical to group 1, into the surrounding brain tissue during tumor removal. Main eligibility criteria are: age of 18 years, unifocal recurrent GBM, amenable to complete or subtotal resection. Dose escalation will be based on the Continual Reassessment Method. The primary objective of the trial is local and systemic safety and tolerability and to determine the maximum tolerated dose (MTD). Secondary objectives are proof of concept (PoC) and Progression-free Survival (PFS) up to 6 months. Discussion This is the first trial with H-1PV in patients with recurrent GBM. The risks for the participants appear well predictable and justified. Furthermore, ParvOryx01 will be the first assessment of combined intratumoral and intravenous application of an oncolytic virus. Due to its study design the trial will not only generate data on the local effect of H-1PV but it will also investigate the penetration of H-1PV into the tumor after systemic delivery and obtain safety data from systemic delivery possibly supporting clinical trials with H-1PV in other, non-CNS malignancies. Trial registration ClinicalTrials.gov Identifier: NCT01301430

Published
2012
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31. Various effects of AAV9-mediated βARKct gene therapy on the heart in dystrophin-deficient (mdx) mice and δ-sarcoglycan-deficient (Sgcd-/-) mice

Author

Bauer, Ralf, primary, Enns, Helene, additional, Jungmann, Andreas, additional, Leuchs, Barbara, additional, Volz, Christian, additional, Schinkel, Stefanie, additional, Koch, Walter J., additional, Raake, Philip W., additional, Most, Patrick, additional, Katus, Hugo A., additional, and Müller, Oliver J., additional

Published
2019
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32. Activation of the human immune system by chemotherapeutic or targeted agents combined with the oncolytic parvovirus H-1

Author

Moehler Markus, Sieben Maike, Roth Susanne, Springsguth Franziska, Leuchs Barbara, Zeidler Maja, Dinsart Christiane, Rommelaere Jean, and Galle Peter R

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Parvovirus H-1 (H-1PV) infects and lyses human tumor cells including melanoma, hepatoma, gastric, colorectal, cervix and pancreatic cancers. We assessed whether the beneficial effects of chemotherapeutic agents or targeted agents could be combined with the oncolytic and immunostimmulatory properties of H-1PV. Methods Using human ex vivo models we evaluated the biological and immunological effects of H-1PV-induced tumor cell lysis alone or in combination with chemotherapeutic or targeted agents in human melanoma cells +/- characterized human cytotoxic T-cells (CTL) and HLA-A2-restricted dendritic cells (DC). Results H-1PV-infected MZ7-Mel cells showed a clear reduction in cell viability of >50%, which appeared to occur primarily through apoptosis. This correlated with viral NS1 expression levels and was enhanced by combination with chemotherapeutic agents or sunitinib. Tumor cell preparations were phagocytosed by DC whose maturation was measured according to the treatment administered. Immature DC incubated with H-1PV-induced MZ7-Mel lysates significantly increased DC maturation compared with non-infected or necrotic MZ7-Mel cells. Tumor necrosis factor-α and interleukin-6 release was clearly increased by DC incubated with H-1PV-induced SK29-Mel tumor cell lysates (TCL) and was also high with DC-CTL co-cultures incubated with H-1PV-induced TCL. Similarly, DC co-cultures with TCL incubated with H-1PV combined with cytotoxic agents or sunitinib enhanced DC maturation to a greater extent than cytotoxic agents or sunitinib alone. Again, these combinations increased pro-inflammatory responses in DC-CTL co-cultures compared with chemotherapy or sunitinib alone. Conclusions In our human models, chemotherapeutic or targeted agents did not only interfere with the pronounced immunomodulatory properties of H-1PV, but also reinforced drug-induced tumor cell killing. H-1PV combined with cisplatin, vincristine or sunitinib induced effective immunostimulation via a pronounced DC maturation, better cytokine release and cytotoxic T-cell activation compared with agents alone. Thus, the clinical assessment of H-1PV oncolytic tumor therapy not only alone but also in combination strategies is warranted.

Published
2011
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33. Preclinical Testing of an Oncolytic Parvovirus in Ewing Sarcoma: Protoparvovirus H-1 Induces Apoptosis and Lytic Infection In Vitro but Fails to Improve Survival In Vivo

Author

Lacroix, Jeannine, primary, Kis, Zoltán, additional, Josupeit, Rafael, additional, Schlund, Franziska, additional, Stroh-Dege, Alexandra, additional, Frank-Stöhr, Monika, additional, Leuchs, Barbara, additional, Schlehofer, Jörg, additional, Rommelaere, Jean, additional, and Dinsart, Christiane, additional

Published
2018
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34. Oncolytic H-1 Parvovirus Shows Safety and Signs of Immunogenic Activity in a First Phase I/IIa Glioblastoma Trial

Author

Geletneky, Karsten, primary, Hajda, Jacek, additional, Angelova, Assia L., additional, Leuchs, Barbara, additional, Capper, David, additional, Bartsch, Andreas J., additional, Neumann, Jan-Oliver, additional, Schöning, Tilman, additional, Hüsing, Johannes, additional, Beelte, Birgit, additional, Kiprianova, Irina, additional, Roscher, Mandy, additional, Bhat, Rauf, additional, von Deimling, Andreas, additional, Brück, Wolfgang, additional, Just, Alexandra, additional, Frehtman, Veronika, additional, Löbhard, Stephanie, additional, Terletskaia-Ladwig, Elena, additional, Fry, Jeremy, additional, Jochims, Karin, additional, Daniel, Volker, additional, Krebs, Ottheinz, additional, Dahm, Michael, additional, Huber, Bernard, additional, Unterberg, Andreas, additional, and Rommelaere, Jean, additional

Published
2017
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38. A non-controlled, single arm, open label, phase II study of intravenous and intratumoral administration of ParvOryx in patients with metastatic, inoperable pancreatic cancer: ParvOryx02 protocol

Author

Hajda, Jacek, primary, Lehmann, Monika, additional, Krebs, Ottheinz, additional, Kieser, Meinhard, additional, Geletneky, Karsten, additional, Jäger, Dirk, additional, Dahm, Michael, additional, Huber, Bernard, additional, Schöning, Tilman, additional, Sedlaczek, Oliver, additional, Stenzinger, Albrecht, additional, Halama, Niels, additional, Daniel, Volker, additional, Leuchs, Barbara, additional, Angelova, Assia, additional, Rommelaere, Jean, additional, Engeland, Christine E., additional, Springfeld, Christoph, additional, and Ungerechts, Guy, additional

Published
2017
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39. A Hepatic GAbp-AMPK Axis Links Inflammatory Signaling to Systemic Vascular Damage

Author

Niopek, Katharina, primary, Üstünel, Bilgen Ekim, additional, Seitz, Susanne, additional, Sakurai, Minako, additional, Zota, Annika, additional, Mattijssen, Frits, additional, Wang, Xiaoyue, additional, Sijmonsma, Tjeerd, additional, Feuchter, Yvonne, additional, Gail, Anna M., additional, Leuchs, Barbara, additional, Niopek, Dominik, additional, Staufer, Oskar, additional, Brune, Maik, additional, Sticht, Carsten, additional, Gretz, Norbert, additional, Müller-Decker, Karin, additional, Hammes, Hans-Peter, additional, Nawroth, Peter, additional, Fleming, Thomas, additional, Conkright, Michael D., additional, Blüher, Matthias, additional, Zeigerer, Anja, additional, Herzig, Stephan, additional, and Berriel Diaz, Mauricio, additional

Published
2017
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41. Bioavailability, Biodistribution, and CNS Toxicity of Clinical-Grade Parvovirus H1 after Intravenous and Intracerebral Injection in Rats

Author

Geletneky, Karsten, Leoni, Anne-Laure, Pohlmeyer-Esch, Gabriele, Loebhard, Stephanie, Leuchs, Barbara, Hoefer, Constance, Jochims, Karin, Dahm, Michael, Huber, Bernard, Rommelaere, Jean, Krebs, Ottheinz, and Hajda, Jacek

Subjects
Central Nervous System, H-1 parvovirus, Oncolytic Virotherapy, Rat Models, Time Factors, Drug Evaluation, Preclinical, Biological Availability, Viral Load, Rats, Liver, DNA, Viral, Injections, Intravenous, Animals, Spleen
Abstract

The autonomous parvovirus H1 (H1PV) is transmitted in rodent populations. The natural host is the rat, in which H1PV infection is pathogenic only in fetuses and newborns. H1PV infection of human cancer cells leads to strong oncolytic effects in preclinical models. In preparation for a clinical trial of H1PV injection in patients with malignant brain tumors, H1PV had to be prepared to Good Manufacturing Practice standards, including extensive toxicology testing in rats. Because the trial involves direct intracerebral injection of H1PV into the tumor and around the resection cavity, possible toxicity to CNS tissue had to be investigated. In addition, quantitative blood levels and the tissue distribution of H1PV after single intracerebral or intravenous injection were measured. Direct injection of H1PV into rat brain at 3 dose levels (maximum, 7.96 × 107 pfu) did not cause any macroscopic or histologic pathology. Furthermore, H1PV infection of the brain did not alter central or autonomous nervous system function. H1PV DNA was detected in almost all organs at 6 h, 48 h, and 14 d after intravenous and intracerebral injection, with the highest levels in liver and spleen. H1PV concentrations in most organs were similar after intravenous and intracerebral injection, indicating high permeability of the blood-brain barrier for this small virus. The current results demonstrate wide organ distribution of H1PV after intravenous or intracerebral injection, confirm that H1PV is nonpathogenic in adult rats even after direct injection into the brain, and form the basis for the ongoing ParvOryx01 clinical trial.

Published
2015

42. Pathology, Organ Distribution, and Immune Response after Single and Repeated Intravenous Injection of Rats with Clinical-Grade Parvovirus H1

Author

Geletneky, Karsten, Leoni, Anne-Laure, Pohlmeyer-Esch, Gabriele, Loebhard, Stephanie, Baetz, Andrea, Leuchs, Barbara, Roscher, Mandy, Hoefer, Constance, Jochims, Karin, Dahm, Michael, Huber, Bernard, Rommelaere, Jean, Krebs, Ottheinz, and Hajda, Jacek

Subjects
H-1 parvovirus, Oncolytic Virotherapy, Rat Models, Dose-Response Relationship, Immunologic, Drug Evaluation, Preclinical, Genome, Viral, Polymerase Chain Reaction, Rats, Parvoviridae Infections, Feces, Liver, Immunoglobulin G, Injections, Intravenous, Animals, Blood Coagulation Tests, Blood Chemical Analysis, Spleen
Abstract

Parvovirus H1 (H1PV) is an autonomous parvovirus that is transmitted in rodent populations. Its natural host is rats. H1PV infection is nonpathogenic except in rat and hamster fetuses and newborns. H1PV infection of human cancer cells caused strong oncolytic effects in preclinical models. For a clinical trial of H1PV in patients with brain tumors, clinical-grade H1PV was produced according to Good Manufacturing Practices. This report focuses on results obtained after a single high-dose intravenous injection of highly purified H1PV in 30 rats and multiple (n = 17) intravenous injections at 3 dose levels in 223 rats. In both studies, no virus-related mortality or macroscopic organ changes related to H1PV occurred. Histopathology after multiple virus injections revealed minimal diffuse bile duct hyperplasia in livers of animals of the highest dose group and germinal center development in spleens of animals from the high-dose group. Liver changes were reversible within a 2-wk recovery period after the last injection. Hematology, blood chemistry, and coagulation analyses did not reveal significant toxicologic changes due to H1PV. Virus injection stimulated the production of IgG antibodies but did not alter mononuclear cell function or induce cytokine release. PCR analysis showed dose-dependent levels of viral genomes in all organs tested. The virus was excreted primarily through feces. These data provide important information regarding H1PV infection in its natural host. Due to the confirmation of the favorable safety profile of H1PV in a permissive animal model, a phase I/IIa clinical trial of H1PV in brain tumor patients could be initiated.

Published
2015

43. HG-87COMBINED APPLICATION OF TEMOZOLOMIDE AND THE ONCOLYTIC PARVOVIRUS H-1 INCREASES CYTOTOXIC EFFECTS IN CELL CULTURE AND ANIMAL MODELS OF PEDIATRIC GLIOBLASTOMA

Author

Lacroix, Jeannine, primary, Josupeit, Rafael, additional, Sorrentino, Domenico, additional, Geiss, Carsten, additional, Leuchs, Barbara, additional, Johann, Pascal, additional, Grill, Jacques, additional, Witt, Olaf, additional, Rommelaere, Jean, additional, and Dinsart, Christiane, additional

Published
2016
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44. Pediatric and Adult High-Grade Glioma Stem Cell Culture Models Are Permissive to Lytic Infection with Parvovirus H-1

Author

Josupeit, Rafael, primary, Bender, Sebastian, additional, Kern, Sonja, additional, Leuchs, Barbara, additional, Hielscher, Thomas, additional, Herold-Mende, Christel, additional, Schlehofer, Jörg, additional, Dinsart, Christiane, additional, Witt, Olaf, additional, Rommelaere, Jean, additional, and Lacroix, Jeannine, additional

Published
2016
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47. Characterization of a Recombinant Adeno-Associated Virus Type 2 Reference Standard Material

Author

Darmon, Christophe, Chtarto, Abdelwahed, Doria, Monica, Conlon, Thomas, Philipsberg, Tina, Beecham, E. Jeffrey, Clark, K. Reed, Leuchs, Barbara, Douar, Anne, Korn, Michael T., Chiorini, John A., Leon, Xavier, Bose, Mahuya, Giacca, Mauro, Francis, Joyce D., Lock, Martin, Korytov, Irina, Müller, Marcus, Blouin-Tavel, Véronique, Moullier, Philippe, Auricchio, Alberto, Ozawa, Keiya, Melas, Catherine, Lux, Gabriele, Byrne, Barry J., McGorray, Susan, Bosch, Fatima, Flotte, Terence R., Francois, Achille, Caton, Tina, Ayuso, Eduard, and Mizukami, Hiroaki

Abstract

A recombinant adeno-associated virus serotype 2 Reference Standard Material (rAAV2 RSM) has been produced and characterized with the purpose of providing a reference standard for particle titer, vector genome titer, and infectious titer for AAV2 gene transfer vectors. Production and purification of the reference material were carried out by helper virus–free transient transfection and chromatographic purification. The purified bulk material was vialed, confirmed negative for microbial contamination, and then distributed for characterization along with standard assay protocols and assay reagents to 16 laboratories worldwide. Using statistical transformation and modeling of the raw data, mean titers and confidence intervals were determined for capsid particles ({X}, 9.18 × 1011 particles/ml; 95% confidence interval [CI], 7.89 × 1011 to 1.05 × 1012 particles/ml), vector genomes ({X}, 3.28 × 1010 vector genomes/ml; 95% CI, 2.70 × 1010 to 4.75 × 1010 vector genomes/ml), transducing units ({X}, 5.09 × 108 transducing units/ml; 95% CI, 2.00 × 108 to 9.60 × 108 transducing units/ml), and infectious units ({X}, 4.37 × 109 TCID50 IU/ml; 95% CI, 2.06 × 109 to 9.26 × 109 TCID50 IU/ml). Further analysis confirmed the identity of the reference material as AAV2 and the purity relative to nonvector proteins as greater than 94%. One obvious trend in the quantitative data was the degree of variation between institutions for each assay despite the relatively tight correlation of assay results within an institution. This relatively poor degree of interlaboratory precision and accuracy was apparent even though attempts were made to standardize the assays by providing detailed protocols and common reagents. This is the first time that such variation between laboratories has been thoroughly documented and the findings emphasize the need in the field for universal reference standards. The rAAV2 RSM has been deposited with the American Type Culture Collection and is available to the scientific community to calibrate laboratory-specific internal titer standards. Anticipated uses of the rAAV2 RSM are discussed.

Published
2010
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48. Manufacturing and characterization of a recombinant adeno-associated virus type 8 reference standard material

Author

Ayuso, Eduard, Leon, Xavier, Bosch, Fatima, Blouin, Veronique, Darmon, Christophe, Moullier, Philippe, Lock, Martin, Alvira, Mauricio M.R., McGorray, Susan, Auricchio, Alberto, Doria, Monica, Bucher, Stephanie, Chtarto, Abdelwahed, Melas, Catherine, Bockstael, Olivier, Clark, Reed K.R., Fountain, Will, Gao, Guangping, Gao, Kai, Giacca, Mauro, Zentilin, Lorena, Kleinschmidt, Juergen, Leuchs, Barbara, Müller, Marcus, Mizukami, Hiroaki, Ozawa, Keiya, Noordman, Yvet, Van Der Linden, Inge, Pythoud, Catherine, Tenenbaum, Liliane, Sumaroka, Marina, Wright, John Fraser, Zhang, Xinhua, Surosky, Richard, Weins, Brigitte, Snyder, Richard O., Ayuso, Eduard, Leon, Xavier, Bosch, Fatima, Blouin, Veronique, Darmon, Christophe, Moullier, Philippe, Lock, Martin, Alvira, Mauricio M.R., McGorray, Susan, Auricchio, Alberto, Doria, Monica, Bucher, Stephanie, Chtarto, Abdelwahed, Melas, Catherine, Bockstael, Olivier, Clark, Reed K.R., Fountain, Will, Gao, Guangping, Gao, Kai, Giacca, Mauro, Zentilin, Lorena, Kleinschmidt, Juergen, Leuchs, Barbara, Müller, Marcus, Mizukami, Hiroaki, Ozawa, Keiya, Noordman, Yvet, Van Der Linden, Inge, Pythoud, Catherine, Tenenbaum, Liliane, Sumaroka, Marina, Wright, John Fraser, Zhang, Xinhua, Surosky, Richard, Weins, Brigitte, and Snyder, Richard O.

Abstract

Gene therapy approaches using recombinant adeno-associated virus serotype 2 (rAAV2) and serotype 8 (rAAV8) have achieved significant clinical benefits. The generation of rAAV Reference Standard Materials (RSM) is key to providing points of reference for particle titer, vector genome titer, and infectious titer for gene transfer vectors. Following the example of the rAAV2RSM, here we have generated and characterized a novel RSM based on rAAV serotype 8. The rAAV8RSM was produced using transient transfection, and the purification was based on density gradient ultracentrifugation. The rAAV8RSM was distributed for characterization along with standard assay protocols to 16 laboratories worldwide. Mean titers and 95% confidence intervals were determined for capsid particles (mean, 5.50×1011 pt/ml; CI, 4.26×1011 to 6.75×1011 pt/ml), vector genomes (mean, 5.75×1011 vg/ml; CI, 3.05×1011 to 1.09×1012 vg/ml), and infectious units (mean, 1.26×109 IU/ml; CI, 6.46×108 to 2.51×109 IU/ml). Notably, there was a significant degree of variation between institutions for each assay despite the relatively tight correlation of assay results within an institution. This outcome emphasizes the need to use RSMs to calibrate the titers of rAAV vectors in preclinical and clinical studies at a time when the field is maturing rapidly. The rAAV8RSM has been deposited at the American Type Culture Collection (VR-1816) and is available to the scientific community., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2014

49. Identification of NY-BR-1-specific CD4+T cell epitopes using HLA-transgenic mice

Author

Gardyan, Adriane, primary, Osen, Wolfram, additional, Zörnig, Inka, additional, Podola, Lilli, additional, Agarwal, Maria, additional, Aulmann, Sebastian, additional, Ruggiero, Eliana, additional, Schmidt, Manfred, additional, Halama, Niels, additional, Leuchs, Barbara, additional, von Kalle, Christof, additional, Beckhove, Philipp, additional, Schneeweiss, Andreas, additional, Jäger, Dirk, additional, and Eichmüller, Stefan B., additional

Published
2014
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50. Manufacturing and Characterization of a Recombinant Adeno-Associated Virus Type 8 Reference Standard Material

Author

Ayuso, Eduard, primary, Blouin, Véronique, additional, Lock, Martin, additional, McGorray, Susan, additional, Leon, Xavier, additional, Alvira, Mauricio R., additional, Auricchio, Alberto, additional, Bucher, Stephanie, additional, Chtarto, Abdelwahed, additional, Clark, K. Reed, additional, Darmon, Christophe, additional, Doria, Monica, additional, Fountain, Will, additional, Gao, Guangping, additional, Gao, Kai, additional, Giacca, Mauro, additional, Kleinschmidt, Juergen, additional, Leuchs, Barbara, additional, Melas, Catherine, additional, Mizukami, Hiroaki, additional, Müller, Marcus, additional, Noordman, Yvet, additional, Bockstael, Olivier, additional, Ozawa, Keiya, additional, Pythoud, Catherine, additional, Sumaroka, Marina, additional, Surosky, Richard, additional, Tenenbaum, Liliane, additional, van der Linden, Inge, additional, Weins, Brigitte, additional, Wright, J. Fraser, additional, Zhang, Xinhua, additional, Zentilin, Lorena, additional, Bosch, Fatima, additional, Snyder, Richard O., additional, and Moullier, Philippe, additional

Published
2014
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