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Sci Transl Med. 2018 Jan 3;10(422). pii: eaam7577. doi: 10.1126/scitranslmed.aam7577.

Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade.

Author information

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
Ohio State University, Comprehensive Cancer Centre, Columbus, OH 43210, USA.
4
Leeds Teaching Hospitals National Health Service Trust, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK.
5
Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA.
6
Oncolytics Biotech, Calgary, Alberta T2N 1X7, Canada.
7
Leeds Institute of Clinical Trials Research, Faculty of Medicine and Health, University of Leeds, Leeds, West Yorkshire LS2 9JT, UK.
8
University College London, London WC1 6BT, UK.
9
University of Surrey, Guildford GU2 7XH, UK.
10
Institute of Cancer Research, 123 Old Brompton Road, London SW7 3RP, UK.
11
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.

Abstract

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.

PMID:
29298869
DOI:
10.1126/scitranslmed.aam7577
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