In a small, window-of-opportunity clinical trial in patients with primary or metastatic brain disease prior to scheduled surgery, Samson et al. demonstrated that intravenous delivery (to overcome the practical difficulties of direct intracranial delivery) of oncolytic reovirus resulted in infection of brain tumor cells, and initiated one or more immune-related events, including PD-L1 expression. In an orthotopic murine model, intravenous reovirus followed by anti-PD-1 therapy significantly increased CD4+ and CD8+ T cell infiltration into the tumor and extended survival.
Immune checkpoint inhibitors, including those targeting programmed cell death protein 1 (PD-1), are reshaping cancer therapeutic strategies. Evidence suggests, however, that tumor response and patient survival are determined by tumor programmed death ligand 1 (PD-L1) expression. We hypothesized that preconditioning of the tumor immune microenvironment using targeted, virus-mediated interferon (IFN) stimulation would up-regulate tumor PD-L1 protein expression and increase cytotoxic T cell infiltration, improving the efficacy of subsequent checkpoint blockade. Oncolytic viruses (OVs) represent a promising form of cancer immunotherapy. For brain tumors, almost all studies to date have used direct intralesional injection of OV, because of the largely untested belief that intravenous administration will not deliver virus to this site. We show, in a window-of-opportunity clinical study, that intravenous infusion of oncolytic human Orthoreovirus (referred to herein as reovirus) leads to infection of tumor cells subsequently resected as part of standard clinical care, both in high-grade glioma and in brain metastases, and increases cytotoxic T cell tumor infiltration relative to patients not treated with virus. We further show that reovirus up-regulates IFN-regulated gene expression, as well as the PD-1/PD-L1 axis in tumors, via an IFN-mediated mechanism. Finally, we show that addition of PD-1 blockade to reovirus enhances systemic therapy in a preclinical glioma model. These results support the development of combined systemic immunovirotherapy strategies for the treatment of both primary and secondary tumors in the brain.
Author Info: (1) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK.
Author Info: (1) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. a.samson@leeds.ac.uk alan.melcher@icr.ac.uk s.c.short@leeds.ac.uk. (2) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (3) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (4) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (5) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (6) Ohio State University, Comprehensive Cancer Centre, Columbus, OH 43210, USA. (7) Leeds Teaching Hospitals National Health Service Trust, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (8) Leeds Teaching Hospitals National Health Service Trust, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (9) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (10) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (11) Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA. (12) Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA. (13) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (14) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (15) Leeds Teaching Hospitals National Health Service Trust, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (16) Leeds Teaching Hospitals National Health Service Trust, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (17) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (18) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (19) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (20) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (21) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (22) Oncolytics Biotech, Calgary, Alberta T2N 1X7, Canada. (23) Leeds Teaching Hospitals National Health Service Trust, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (24) Leeds Institute of Clinical Trials Research, Faculty of Medicine and Health, University of Leeds, Leeds, West Yorkshire LS2 9JT, UK. (25) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (26) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (27) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (28) University College London, London WC1 6BT, UK. (29) University College London, London WC1 6BT, UK. (30) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (31) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (32) University of Surrey, Guildford GU2 7XH, UK. (33) Institute of Cancer Research, 123 Old Brompton Road, London SW7 3RP, UK. (34) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (35) Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA. (36) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (37) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (38) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. a.samson@leeds.ac.uk alan.melcher@icr.ac.uk s.c.short@leeds.ac.uk. (39) Institute of Cancer Research, 123 Old Brompton Road, London SW7 3RP, UK. a.samson@leeds.ac.uk alan.melcher@icr.ac.uk s.c.short@leeds.ac.uk.
