Oncolytic Newcastle disease virus activation of the innate immune response and priming of antitumor adaptive responses in vitro

Shannon Burke,Justine Whitworth,Amy Shergold,Danielle K Carroll,Matthew J Elder,Hong Jin,James Harper,Xing Cheng,Robert W Wilkinson

doi:10.1007/s00262-020-02495-x

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 colony-stimulating 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.

Highlights

Despite advances in targeted therapies and, more recently, IO drugs such as immune checkpoint inhibitors, cancer remains a leading cause of mortality [1]
To investigate the immunomodulatory activity of Newcastle disease virus (NDV), Peripheral blood mononuclear cells (PBMCs) isolated from healthy human donors were infected with MEDI5395
A surrogate NDV expressing murine GMCSF (NDVmuGM-CSF), which does not cross-react with the human granulocyte–macrophage colonystimulating factor (GM-CSF) receptor [14], was used to assess the contribution of the therapeutic GM-CSF transgene in this setting

Summary

Introduction

Despite advances in targeted therapies (small molecules and antibodies) and, more recently, IO drugs such as immune checkpoint inhibitors, cancer remains a leading cause of mortality [1]. A diverse class of viruses broadly characterized historically by their tumor cell-killing potential, have re-emerged as a promising option for cancer therapy with the recent clinical approval of a modified herpesvirus, talimogene laherparepvec (TVEC), for malignant melanoma [2]. Driving this is the realization that OVs demonstrate an ability to activate the immune system coincident with tumor cell killing. The approval of TVEC in patients with metastatic melanoma and the recent demonstration that its use could potentiate current IO therapy provide a further rationale for development of other OV candidates [ 5]. Limitations of the current OV strategies, such as their restriction to intratumoral delivery, indicate the need to develop OVs with broader applicability

Methods

Results

Conclusion