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Intravenous Delivery of Oncolytic Reovirus to Brain Tumor Patients Immunologically Primes for Subsequent Checkpoint Blockade

Samson, A, Scott, K, Taggart, D, West, E, Wilson, E, Nuovo, G, Thomson, S, Corns, R, Mathew, R, Fuller, M , Kottke, T, Thompson, J, Ilett, E, Cockle, J, van Hille, P, Sivakumar, G, Polson, E, Turnbull, S, Appleton, E, Migneco, G, Rose, A, Coffey, M, Beirne, D, Collinson, F, Ralph, C, Anthoney, D, Twelves, C, Furness, A, Quezada, S, Wurdak, H, Errington-Mais, F, Pandha, Hardev, Harrington, K, Selby, P, Vile, R, Griffin, S, Stead, L, Short, S and Melcher, A (2018) Intravenous Delivery of Oncolytic Reovirus to Brain Tumor Patients Immunologically Primes for Subsequent Checkpoint Blockade Science Translational Medicine, 10 (422), eaam7577.

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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 upregulate 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 (i.v.) administration will not deliver virus to this site. Here we show, in a window-of-opportunity clinical study, that i.v. 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 (HGG) and in brain metastases, and increases cytotoxic T cell tumor infiltration relative to patients not treated with virus. We further show that reovirus upregulates 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.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
Samson, A
Scott, K
Taggart, D
West, E
Wilson, E
Nuovo, G
Thomson, S
Corns, R
Mathew, R
Fuller, M
Kottke, T
Thompson, J
Ilett, E
Cockle, J
van Hille, P
Sivakumar, G
Polson, E
Turnbull, S
Appleton, E
Migneco, G
Rose, A
Coffey, M
Beirne, D
Collinson, F
Ralph, C
Anthoney, D
Twelves, C
Furness, A
Quezada, S
Wurdak, H
Errington-Mais, F
Harrington, K
Selby, P
Vile, R
Griffin, S
Stead, L
Short, S
Melcher, A
Date : 3 January 2018
DOI : 10.1126/scitranslmed.aam7577
Copyright Disclaimer : Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. This is an article distributed under the terms of the Science Journals Default License.
Related URLs :
Depositing User : Melanie Hughes
Date Deposited : 15 Jan 2018 11:53
Last Modified : 16 Jan 2019 19:07

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