Low-dose oncolytic adenovirus therapy overcomes tumor-induced immune suppression and sensitizes intracranial gliomas to anti-PD-1 therapy

Zineb Belcaid; Cor Berrevoets; John Choi; Edward van Beelen; Eftychia Stavrakaki; Tessa Pierson; Jenneke Kloezeman; Denis Routkevitch; Mariëlle van der Kaaij; Alicia van der Ploeg; Dimitrios Mathios; Stefan Sleijfer; Clemens Dirven; Michael Lim; Reno Debets; Martine L M Lamfers

doi:10.1093/noajnl/vdaa011

Low-dose oncolytic adenovirus therapy overcomes tumor-induced immune suppression and sensitizes intracranial gliomas to anti-PD-1 therapy

Neurooncol Adv. 2020 Feb 3;2(1):vdaa011. doi: 10.1093/noajnl/vdaa011. eCollection 2020 Jan-Dec.

Authors

Zineb Belcaid^{1

2}, Cor Berrevoets², John Choi³, Edward van Beelen¹, Eftychia Stavrakaki¹, Tessa Pierson¹, Jenneke Kloezeman¹, Denis Routkevitch³, Mariëlle van der Kaaij¹, Alicia van der Ploeg¹, Dimitrios Mathios³, Stefan Sleijfer², Clemens Dirven¹, Michael Lim³, Reno Debets², Martine L M Lamfers¹

Affiliations

¹ Department of Neurosurgery, Brain Tumor Center, Erasmus University Medical Center, Rotterdam, The Netherlands.
² Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
³ Department of Neurosurgery, Johns Hopkins Hospital, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Abstract

Background: The tumor-selective human adenovirus Delta24-RGD is currently under investigation in phase II clinical trials for patients with recurrent glioblastoma (GBM). To improve treatments for patients with GBM, we explored the potential of combining Delta24-RGD with antibodies targeting immune checkpoints.

Methods: C57BL/6 mice were intracranially injected with GL261 cells and treated with a low dose of Delta24-RGD virus. The expression dynamics of 10 co-signaling molecules known to affect immune activity was assessed in tumor-infiltrating immune cells by flow cytometry after viral injection. The antitumor activity was measured by tumor cell killing and IFNγ production in co-cultures. Efficacy of the combination viro-immunotherapy was tested in vitro and in the GL261 and CT2A orthotopic mouse GBM models. Patient-derived GBM cell cultures were treated with Delta24-RGD to assess changes in PD-L1 expression induced by virus infection.

Results: Delta24-RGD therapy increased intratumoral CD8⁺ T cells expressing Inducible T-cell co-stimulator (ICOS) and PD-1. Functionality assays confirmed a significant positive correlation between tumor cell lysis and IFNγ production in ex vivo cultures (Spearman r = 0.9524; P < .01). Co-cultures significantly increased IFNγ production upon treatment with PD-1 blocking antibodies. In vivo, combination therapy with low-dose Delta24-RGD and anti-PD-1 antibodies significantly improved outcome compared to single-agent therapy in both syngeneic mouse glioma models and increased PD-1⁺ tumor-infiltrating CD8⁺ T cells. Delta24-RGD infection induced tumor-specific changes in PD-L1 expression in primary GBM cell cultures.

Conclusions: This study demonstrates the potential of using low-dose Delta24-RGD therapy to sensitize glioma for combination with anti-PD-1 antibody therapy.

Keywords: Delta24-RGD; PD-1; glioma; immunotherapy; oncolytic virotherapy.