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

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.

Oncolytic herpes simplex virus HF10 (canerpaturev) promotes accumulation of CD8+PD‐1− tumor‐infiltrating T cells in PD‐L1‐enriched tumor microenvironment

“…However, injection of a low dose of another oncolytic adenovirus, Delta24‐RGD, increases the density of intratumoral PD‐1 + T cells, which are inversely correlated with ex vivo T‐cell activity. In that study, low‐dose adenovirus was injected one time into gliomas 30 . By contrast, in this study, 5 × 10 5 PFU C‐REV was injected three times.…”

Oncolytic Virus Therapy Alters the Secretome of Targeted Glioblastoma Cells

“…During the last decade or so, oncolytic viruses’ therapeutic usage has evolved from primarily antitumor cytotoxicity, toward enhancing the immune response [ 6 , 60 , 61 ]. The engineering of the oncolytic virus, and clinical trials [ 62 ] with oncolytic virus immunotherapy have provided early-stage results showing that some tumors respond by changing the “cold” tumor immune environment toward a “hot” one in response to the oncolytic virus [ 63 , 64 ].…”

Oncolytic Viruses as a Platform for the Treatment of Malignant Brain Tumors

“…The treatment of C57/BL6 mice bearing GL261 tumors with a systemic infusion of a GM-CSF-expressing reovirus followed by anti-PD-1 antibodies resulted in improved survival as compared to single-agent therapies. In-line with this, Belcaid et al recently demonstrated that low doses of the oncolytic adenovirus DNX-2401 (or Delta24-RGD) are sufficient to significantly alter the immune microenvironment in murine glioma, mostly by the upregulation of PD-1 and ICOS expression on CD8+ T cells [ 108 ]. Additionally, the brain tumor size was inversely correlated with the PD-1+ T-cell population in the tumor, suggesting that tumor regression is correlated with the local presence of PD-1+ T cells.…”

“…Additionally, the brain tumor size was inversely correlated with the PD-1+ T-cell population in the tumor, suggesting that tumor regression is correlated with the local presence of PD-1+ T cells. Indeed, Delta24-RGD, in combination with anti-PD-1, significantly improved the overall survival in GL261 and CT2A orthotopic mouse models [ 108 ].…”