Intratumoral modulation of the inducible co-stimulator ICOS by recombinant oncolytic virus promotes systemic anti-tumour immunity

Dmitriy Zamarin, Rikke B. Holmgaard, Jacob Ricca, Tamar Plitt, Peter Palese, Padmanee Sharma, Taha Merghoub, Jedd D. Wolchok and James P. Allison
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Dmitriy Zamarin: Memorial Sloan Kettering Cancer Center
Rikke B. Holmgaard: Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center
Jacob Ricca: Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center
Tamar Plitt: Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center
Peter Palese: Icahn School of Medicine at Mount Sinai
Padmanee Sharma: MD Anderson Cancer Center
Taha Merghoub: Weill Cornell Medical College
Jedd D. Wolchok: Memorial Sloan Kettering Cancer Center
James P. Allison: MD Anderson Cancer Center

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Emerging data suggest that locoregional cancer therapeutic approaches with oncolytic viruses can lead to systemic anti-tumour immunity, although the appropriate targets for intratumoral immunomodulation using this strategy are not known. Here we find that intratumoral therapy with Newcastle disease virus (NDV), in addition to the activation of innate immunity, upregulates the expression of T-cell co-stimulatory receptors, with the inducible co-stimulator (ICOS) being most notable. To explore ICOS as a direct target in the tumour, we engineered a recombinant NDV-expressing ICOS ligand (NDV-ICOSL). In the bilateral flank tumour models, intratumoral administration of NDV-ICOSL results in enhanced infiltration with activated T cells in both virus-injected and distant tumours, and leads to effective rejection of both tumours when used in combination with systemic CTLA-4 blockade. These findings highlight that intratumoral immunomodulation with an oncolytic virus expressing a rationally selected ligand can be an effective strategy to drive systemic efficacy of immune checkpoint blockade.

Date: 2017
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DOI: 10.1038/ncomms14340

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