Nanobody-based retargeting of an oncolytic herpesvirus for eliminating CXCR4+ GBM cells: A proof of principle

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

doi:10.1016/j.omto.2022.06.002

Nanobody-based retargeting of an oncolytic herpesvirus for eliminating CXCR4⁺ GBM cells: A proof of principle

Mol Ther Oncolytics. 2022 Jun 6:26:35-48. doi: 10.1016/j.omto.2022.06.002. eCollection 2022 Sep 15.

Authors

Affiliations

¹ Laboratory of Virology and Immunology, GIGA Infection, Inflammation and Immunity (GIGA I3), University of Liège, 4000 Liège, Belgium.
² Laboratory of Nervous System Disorders and Therapy, GIGA-Neurosciences, University of Liège, 4000 Liège, Belgium.
³ Department of Neurosurgery, CHU of Liège, 4000 Liège, Belgium.
⁴ Department of Neurology, CHU of Liège, 4000 Liège, Belgium.

Abstract

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.

Keywords: CXCR4; GBM; GSC; HSV; glioblastoma; glioblastoma stem-like cells; nanobody; oncolytic herpesvirus; virotherapy; virus retargeting.