Superior infectivity of the fiber chimeric oncolytic adenoviruses Ad5/35 and Ad5/3 over Ad5-delta-24-RGD in primary glioma cultures

Aleksei A Stepanenko; Anastasiia O Sosnovtseva; Marat P Valikhov; Anastasia A Chernysheva; Sergey A Cherepanov; Gaukhar M Yusubalieva; Zsolt Ruzsics; Anastasiia V Lipatova; Vladimir P Chekhonin

doi:10.1016/j.omto.2021.12.013

Superior infectivity of the fiber chimeric oncolytic adenoviruses Ad5/35 and Ad5/3 over Ad5-delta-24-RGD in primary glioma cultures

Mol Ther Oncolytics. 2021 Dec 21:24:230-248. doi: 10.1016/j.omto.2021.12.013. eCollection 2022 Mar 17.

Authors

Affiliations

¹ Department of Fundamental and Applied Neurobiology, V.P. Serbsky National Medical Research Center of Psychiatry and Narcology, The Ministry of Health of the Russian Federation, Kropotkinsky Lane 23, 119034 Moscow, Russia.
² Department of Medical Nanobiotechnology, Institute of Translational Medicine, N.I. Pirogov Russian National Research Medical University, The Ministry of Health of the Russian Federation, Ostrovitianov Str. 1, 117997 Moscow, Russia.
³ Federal Research and Clinical Center for Specialized Types of Medical Care and Medical Technologies of the FMBA of Russia, Moscow, Russia.
⁴ Institute of Virology, Medical Center, University of Freiburg, Freiburg, Germany.
⁵ Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁶ Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.

Abstract

Ad5-delta-24-RGD is currently the most clinically advanced recombinant adenovirus (rAd) for glioma therapy. We constructed a panel of fiber-modified rAds (Ad5RGD, Ad5/3, Ad5/35, Ad5/3RGD, and Ad5/35RGD, all harboring the delta-24 modification) and compared their infectivity, replication, reproduction, and cytolytic efficacy in human and rodent glioma cell lines and short-term cultures from primary gliomas. In human cells, both Ad5/35-delta-24 and Ad5/3-delta-24 displayed superior infectivity and cytolytic efficacy over Ad5-delta-24-RGD, while Ad5/3-delta-24-RGD and Ad5/35-delta-24-RGD did not show further improvements in efficacy. The expression of the adenoviral receptors/coreceptors CAR, DSG2, and CD46 and the integrins αVβ3/αVβ5 did not predict the relative cytolytic efficacy of the fiber-modified rAds. The cytotoxicity of the fiber-modified rAds in human primary normal cultures of different origins and in primary glioma cultures was comparable, indicating that the delta-24 modification did not confer tumor cell selectivity. We also revealed that CT-2A and GL261 glioma cells might be used as murine cell models for the fiber chimeric rAds in vitro and in vivo. In GL261 tumor-bearing mice, Ad5/35-delta-24, armed with the immune costimulator OX40L as the E2A/DBP-p2A-mOX40L fusion, produced long-term survivors, which were able to reject tumor cells upon rechallenge. Our data underscore the potential of local Ad5/35-delta-24-based immunovirotherapy for glioblastoma treatment.

Keywords: Ad5-delta-24-RGD; Ad5/3; Ad5/35; DNX-2401; fiber chimeric adenovirus; gene therapy; glioblastoma; glioma; immunotherapy; oncolytic virotherapy.