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

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.

A guide to cancer immunotherapy: from T cell basic science to clinical practice

“…For example, autologous tumour cells infected with Newcastle disease virus have been used in one type of cancer vaccine that has demon strated success in preclinical models of metastatic lym phoma and melanoma 216,217 . Modified Newcastle disease virusbased vaccines have been engineered to express granulocyte-macrophage colonystimulating factor (GMCSF) in attempts to enhance efficacy 218 . Synergism of vaccine approaches with checkpoint blockade agents has also been demonstrated in some preclinical studies of melanoma 46,219 .…”

Newcastle Disease Virus at the Forefront of Cancer Immunotherapy

“…Given its ability to activate antigen-presenting cells, granulocyte-macrophage colony stimulating factor (GM-CSF) has been explored as a therapeutic transgene within the context of multiple oncolytic viruses, and T-VEC, an oncolytic herpes simplex virus expressing GM-CSF, was approved by the FDA for treatment of metastatic melanoma [74]. A recombinant strain based on the mesogenic NDV 73T strain currently in clinical development, MEDI5395, expressing human GM-CSF was recently shown to increase secretion of pro-inflammatory cytokines such as IFN-α, IL-6, IL-8, and TNF-α in PBMC samples from healthy volunteers, and stimulated PBMCs to exert antitumor effects in vitro [83]. In addition, infection of dendritic cells led to their maturation, and co-culture of dendritic cells with allogeneic T cells increased the levels of T cell effector cytokines IL-2 and IFN-γ [83].…”

Targeting Tumor-Associated Macrophages in Anti-Cancer Therapies: Convincing the Traitors to Do the Right Thing

“…Within the last decades the controlled application of oncolytic viruses (OV) has emerged as an attractive therapeutic approach, owing to a preferential infection and killing of cancer cells, which results in innate antitumor immune responses and immunological memory [ 121 ]. In a similar manner to ICD or RT, OVs (i.e., influenza A, herpes simplex virus encoding GM-CSF, or adenovirus Delta24-RGD) induced the release of tumor-associated antigens and immunostimulatory signals, which promote TAMs polarization towards M1-like antitumor effectors [ 122 ]. Other approaches to induce ICD activation, such as RIG-1 activation, are currently being tested in preclinical and clinical studies alone or in combination with ICIs [ 123 ].…”

“…In vivo, the STING agonists changed the FcγR A:I ratio and enhanced the efficacy of anti-CD20 mAb therapy [ 138 ]. Of note, the use of TLR or STING agonists, as adjuvants, alone, or in combination has been also evaluated in the context of cancer vaccination in preclinical and clinical trials [ 122 , 139 ].…”