Low-dose oncolytic adenovirus therapy overcomes tumor-induced immune suppression and sensitizes intracranial gliomas to anti-PD-1 therapy
Rattachement africain : nl, us. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
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.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Low-dose oncolytic adenovirus therapy overcomes tumor-induced immune suppression and sensitizes intracranial gliomas to anti-PD-1 therapy
- Date Crossref
- 01/01/2020
- Éditeur
- Oxford University Press (OUP)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Erasmus MC pays non établi dans la noticeÉtablissement de santé
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Erasmus MC Cancer Institute pays non établi dans la noticeÉtablissement de santé
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Johns Hopkins University Department of Neurosurgery pays non établi dans la noticeUniversité ou école supérieure
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Johns Hopkins Medicine pays non établi dans la noticeÉtablissement de santé
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Johns Hopkins Hospital pays non établi dans la noticeÉtablissement de santé
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Erasmus University Medical Center Department of Neurosurgery pays non établi dans la noticeUniversité ou école supérieure
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Laboratory of Tumor Immunology pays non établi dans la noticeStructure de recherche
Erasmus MC, Erasmus MC Cancer Institute et Department of Neurosurgery — Johns Hopkins University, avec 4 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.