Nanobody-based retargeting of an oncolytic herpesvirus for eliminating CXCR4+ GBM cells: A proof of principle
Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, which remains difficult to cure. The very high recurrence rate has been partly attributed to the presence of GBM stem-like cells (GSCs) within the tumors, which have been associated with elevated chemokine receptor 4 (CXCR4) ex...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-09-01
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| Series: | Molecular Therapy: Oncolytics |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S237277052200078X |
| _version_ | 1811242710745481216 |
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| author | Judit Sanchez Gil Maxime Dubois Virginie Neirinckx Arnaud Lombard Natacha Coppieters Paolo D’Arrigo Damla Isci Therese Aldenhoff Benoit Brouwers Cédric Lassence Bernard Rogister Marielle Lebrun Catherine Sadzot-Delvaux |
| author_facet | Judit Sanchez Gil Maxime Dubois Virginie Neirinckx Arnaud Lombard Natacha Coppieters Paolo D’Arrigo Damla Isci Therese Aldenhoff Benoit Brouwers Cédric Lassence Bernard Rogister Marielle Lebrun Catherine Sadzot-Delvaux |
| author_sort | Judit Sanchez Gil |
| collection | DOAJ |
| description | Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, which remains difficult to cure. The very high recurrence rate has been partly attributed to the presence of GBM stem-like cells (GSCs) within the tumors, which have been associated with elevated chemokine receptor 4 (CXCR4) expression. CXCR4 is frequently overexpressed in cancer tissues, including GBM, and usually correlates with a poor prognosis. We have created a CXCR4-retargeted oncolytic herpesvirus (oHSV) by insertion of an anti-human CXCR4 nanobody in glycoprotein D of an attenuated HSV-1 (ΔICP34.5, ΔICP6, and ΔICP47), thereby describing a proof of principle for the use of nanobodies to target oHSVs toward specific cellular entities. Moreover, this virus has been armed with a transgene expressing a soluble form of TRAIL to trigger apoptosis. In vitro, this oHSV infects U87MG CXCR4+ and patient-derived GSCs in a CXCR4-dependent manner and, when armed, triggers apoptosis. In a U87MG CXCR4+ orthotopic xenograft mouse model, this oHSV slows down tumor growth and significantly improves mice survival. Customizing oHSVs with diverse nanobodies for targeting multiple proteins appears as an interesting approach for tackling the heterogeneity of GBM, especially GSCs. Altogether, our study must be considered as a proof of principle and a first step toward personalized GBM virotherapies to complement current treatments. |
| first_indexed | 2024-04-12T13:54:55Z |
| format | Article |
| id | doaj.art-78ee24bc996e4ceba374cb5ce3da0b94 |
| institution | Directory Open Access Journal |
| issn | 2372-7705 |
| language | English |
| last_indexed | 2024-04-12T13:54:55Z |
| publishDate | 2022-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncolytics |
| spelling | doaj.art-78ee24bc996e4ceba374cb5ce3da0b942022-12-22T03:30:24ZengElsevierMolecular Therapy: Oncolytics2372-77052022-09-01263548Nanobody-based retargeting of an oncolytic herpesvirus for eliminating CXCR4+ GBM cells: A proof of principleJudit Sanchez Gil0Maxime Dubois1Virginie Neirinckx2Arnaud Lombard3Natacha Coppieters4Paolo D’Arrigo5Damla Isci6Therese Aldenhoff7Benoit Brouwers8Cédric Lassence9Bernard Rogister10Marielle Lebrun11Catherine Sadzot-Delvaux12Laboratory of Virology and Immunology, GIGA Infection, Inflammation and Immunity (GIGA I3), University of Liège, 4000 Liège, BelgiumLaboratory of Virology and Immunology, GIGA Infection, Inflammation and Immunity (GIGA I3), University of Liège, 4000 Liège, BelgiumLaboratory of Nervous System Disorders and Therapy, GIGA-Neurosciences, University of Liège, 4000 Liège, BelgiumLaboratory of Nervous System Disorders and Therapy, GIGA-Neurosciences, University of Liège, 4000 Liège, Belgium; Department of Neurosurgery, CHU of Liège, 4000 Liège, BelgiumLaboratory of Nervous System Disorders and Therapy, GIGA-Neurosciences, University of Liège, 4000 Liège, BelgiumLaboratory of Virology and Immunology, GIGA Infection, Inflammation and Immunity (GIGA I3), University of Liège, 4000 Liège, BelgiumLaboratory of Nervous System Disorders and Therapy, GIGA-Neurosciences, University of Liège, 4000 Liège, BelgiumLaboratory of Nervous System Disorders and Therapy, GIGA-Neurosciences, University of Liège, 4000 Liège, BelgiumLaboratory of Nervous System Disorders and Therapy, GIGA-Neurosciences, University of Liège, 4000 Liège, BelgiumLaboratory of Virology and Immunology, GIGA Infection, Inflammation and Immunity (GIGA I3), University of Liège, 4000 Liège, BelgiumLaboratory of Nervous System Disorders and Therapy, GIGA-Neurosciences, University of Liège, 4000 Liège, Belgium; Department of Neurology, CHU of Liège, 4000 Liège, BelgiumLaboratory of Virology and Immunology, GIGA Infection, Inflammation and Immunity (GIGA I3), University of Liège, 4000 Liège, BelgiumLaboratory of Virology and Immunology, GIGA Infection, Inflammation and Immunity (GIGA I3), University of Liège, 4000 Liège, Belgium; Corresponding author Catherine Sadzot-Delvaux, Laboratory of Virology and Immunology, GIGA Infection, Inflammation and Immunity (GIGA I3), University of Liège, 11 Avenue de l’Hôpital, 4000 Liège, Belgium.Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, which remains difficult to cure. The very high recurrence rate has been partly attributed to the presence of GBM stem-like cells (GSCs) within the tumors, which have been associated with elevated chemokine receptor 4 (CXCR4) expression. CXCR4 is frequently overexpressed in cancer tissues, including GBM, and usually correlates with a poor prognosis. We have created a CXCR4-retargeted oncolytic herpesvirus (oHSV) by insertion of an anti-human CXCR4 nanobody in glycoprotein D of an attenuated HSV-1 (ΔICP34.5, ΔICP6, and ΔICP47), thereby describing a proof of principle for the use of nanobodies to target oHSVs toward specific cellular entities. Moreover, this virus has been armed with a transgene expressing a soluble form of TRAIL to trigger apoptosis. In vitro, this oHSV infects U87MG CXCR4+ and patient-derived GSCs in a CXCR4-dependent manner and, when armed, triggers apoptosis. In a U87MG CXCR4+ orthotopic xenograft mouse model, this oHSV slows down tumor growth and significantly improves mice survival. Customizing oHSVs with diverse nanobodies for targeting multiple proteins appears as an interesting approach for tackling the heterogeneity of GBM, especially GSCs. Altogether, our study must be considered as a proof of principle and a first step toward personalized GBM virotherapies to complement current treatments.http://www.sciencedirect.com/science/article/pii/S237277052200078XvirotherapyHSVglioblastomaglioblastoma stem-like cellsGBMGSC |
| spellingShingle | Judit Sanchez Gil Maxime Dubois Virginie Neirinckx Arnaud Lombard Natacha Coppieters Paolo D’Arrigo Damla Isci Therese Aldenhoff Benoit Brouwers Cédric Lassence Bernard Rogister Marielle Lebrun Catherine Sadzot-Delvaux Nanobody-based retargeting of an oncolytic herpesvirus for eliminating CXCR4+ GBM cells: A proof of principle Molecular Therapy: Oncolytics virotherapy HSV glioblastoma glioblastoma stem-like cells GBM GSC |
| title | Nanobody-based retargeting of an oncolytic herpesvirus for eliminating CXCR4+ GBM cells: A proof of principle |
| title_full | Nanobody-based retargeting of an oncolytic herpesvirus for eliminating CXCR4+ GBM cells: A proof of principle |
| title_fullStr | Nanobody-based retargeting of an oncolytic herpesvirus for eliminating CXCR4+ GBM cells: A proof of principle |
| title_full_unstemmed | Nanobody-based retargeting of an oncolytic herpesvirus for eliminating CXCR4+ GBM cells: A proof of principle |
| title_short | Nanobody-based retargeting of an oncolytic herpesvirus for eliminating CXCR4+ GBM cells: A proof of principle |
| title_sort | nanobody based retargeting of an oncolytic herpesvirus for eliminating cxcr4 gbm cells a proof of principle |
| topic | virotherapy HSV glioblastoma glioblastoma stem-like cells GBM GSC |
| url | http://www.sciencedirect.com/science/article/pii/S237277052200078X |
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