Oncolytic Newcastle disease virus activation of the innate immune response and priming of antitumor adaptive responses i
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ORIGINAL ARTICLE
Oncolytic Newcastle disease virus activation of the innate immune response and priming of antitumor adaptive responses in vitro Shannon Burke1 · Amy Shergold1 · Matthew J. Elder1 · Justine Whitworth1 · Xing Cheng2,3 · Hong Jin2 · Robert W. Wilkinson1 · James Harper1 · Danielle K. Carroll1 Received: 23 September 2019 / Accepted: 20 January 2020 © The Author(s) 2020
Abstract Oncolytic virus (OV) therapy is an emerging approach with the potential to redefine treatment options across a range of cancer indications and in patients who remain resistant to existing standards of care, including immuno-oncology (IO) drugs. MEDI5395, a recombinant Newcastle disease virus (NDV), engineered to express granulocyte–macrophage colonystimulating factor (GM-CSF), exhibits potent oncolytic activity. It was hypothesized that activation of immune cells by MEDI5395, coupled with its oncolytic activity, would enhance the priming of antitumor immunity. Using MEDI5395 and recombinant NDVs encoding fluorescent reporter genes, we demonstrated preferential virus uptake and non-productive infection in myeloid cells, including monocytes, macrophages, and dendritic cells (DCs). Infection resulted in immune-cell activation, with upregulation of cell surface activation markers (e.g., CD80, PD-L1, HLA-DR) and secretion of proinflammatory cytokines (IFN-α2a, IL-6, IL-8, TNF-α). Interestingly, in vitro M2-polarized macrophages were more permissive to virus infection than were M1-polarized macrophages. In a co-culture system, infected myeloid cells were effective virus vectors and mediated the transfer of infectious NDV particles to tumor cells, resulting in cell death. Furthermore, NDV-infected DCs stimulated greater proliferation of allogeneic T cells than uninfected DCs. Antigens released after NDV-induced tumor cell lysis were cross-presented by DCs and drove activation of tumor antigen-specific autologous T cells. MEDI5395 therefore exhibited potent immunostimulatory activity and an ability to enhance antigen-specific T-cell priming. This, coupled with its tumor-selective oncolytic capacity, underscores the promise of MEDI5395 as a multimodal therapeutic, with potential to both enhance current responding patient populations and elicit de novo responses in resistant patients. Keywords Newcastle disease virus · Oncolytic virus · Immunotherapy · MEDI5395 Abbreviations hGM-CSF Human granulocyte–macrophage colony-stimulating factor IO Immuno-oncology IV Intravenous Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00262-020-02495-x) contains supplementary material, which is available to authorized users. * Shannon Burke [email protected] 1
Oncology R&D, AstraZeneca, Aaron Klug Building, Granta Park, Cambridge CB21 6GH, UK
2
BioPharmaceuticals R&D, Clinical Pharmacology & Safety Sciences, AstraZeneca, South San Francisco, CA, USA
3
Present Address: Meissa Vaccines, JLABS, 329 Oyster Point Boulevard, 3rd Floor, South San Francisco, CA, USA
M-CSF Macroph
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