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


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.

SUBMITTER: Samson A 

PROVIDER: S-EPMC6276984 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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

Samson Adel A   Scott Karen J KJ   Taggart David D   West Emma J EJ   Wilson Erica E   Nuovo Gerard J GJ   Thomson Simon S   Corns Robert R   Mathew Ryan K RK   Fuller Martin J MJ   Kottke Timothy J TJ   Thompson Jill M JM   Ilett Elizabeth J EJ   Cockle Julia V JV   van Hille Philip P   Sivakumar Gnanamurthy G   Polson Euan S ES   Turnbull Samantha J SJ   Appleton Elizabeth S ES   Migneco Gemma G   Rose Ailsa S AS   Coffey Matthew C MC   Beirne Deborah A DA   Collinson Fiona J FJ   Ralph Christy C   Alan Anthoney D D   Twelves Christopher J CJ   Furness Andrew J AJ   Quezada Sergio A SA   Wurdak Heiko H   Errington-Mais Fiona F   Pandha Hardev H   Harrington Kevin J KJ   Selby Peter J PJ   Vile Richard G RG   Griffin Stephen D SD   Stead Lucy F LF   Short Susan C SC   Melcher Alan A AA  

Science translational medicine 20180101 422


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 infiltr  ...[more]

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