Oncolytic Newcastle disease virus expressing a checkpoint inhibitor as a radioenhancing agent for murine melanoma

EBioMedicine. 2019 Nov;49:96-105. doi: 10.1016/j.ebiom.2019.10.032. Epub 2019 Oct 29.

Abstract

Background: Monoclonal antibodies (mAbs) targeting negative regulators, or checkpoint molecules (e.g. PD1/PD-L1 & CTLA4), of anti-tumoural T cells have demonstrated clinical efficacy in treating several neoplastic diseases. While many patients enjoy remarkable responses to checkpoint inhibitors, a majority show adverse effects. Understanding how checkpoint inhibitors may augment established chemotherapy or radiotherapy regimens or other immunotherapies like oncolytic viruses may lead to better clinical outcomes measured by improved efficacy with reduced toxicity. Here, we assess how Newcastle disease virus (NDV), an oncolytic virus in clinical testing, may interact with radiotherapy to enhance checkpoint inhibitor blockade.

Methods: An immunocompetent B16-F10 murine melanoma model, generally considered to be a poorly immunogenic or "cold" tumour, was utilised to query whether combining localised radiotherapy with NDV may be more effective than either therapy alone in controlling tumours in mice treated with anti-PD1 or anti-CTLA4 monoclonal antibodies. We also investigated whether localised administration of a checkpoint inhibitor through an intratumoural injection of NDV that expresses anti-CTLA4 single-chain variable fragment (scFv) is comparable to systemic administration of anti-CTLA4 when combined with radiation in mediating its anti-tumour efficacy. Response rates were characterised by measuring tumour size over time, observation of complete tumour regression, and overall survival.

Findings: Our results show that combining NDV plus radiotherapy with checkpoint inhibitors (PD1 or CTLA4 targeted mAbs) results in significantly better complete tumour regression rates with an abscopal effect in a murine model of melanoma than either single therapy combined with checkpoint inhibitors. Finally, we also show that localised administration of a recombinant NDV expressing anti-CTLA4 plus radiation is comparable to systemic anti-CTLA4 plus radiation in mediating its anti-tumour effect as assayed by survival benefit.

Interpretation: Our results show that oncolytic NDV plus radiotherapy work together with checkpoint inhibitors to enhance tumour clearance of murine melanoma. NDV is an effective radiotherapy dose-sparing and immunotherapeutic agent capable of transgenic, in vivo expression of an anti-CTLA4 targeted scFv antibody with the potential to spare systemic exposure.

Funding: The National Institutes of Health grant HHSN272201400008C supported the work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Keywords: Cancer immunotherapy; Checkpoint inhibitors; Newcastle disease virus; Oncolytic viruses; Radiation therapy; Radioenhancer; Radiosensitiser.

MeSH terms

  • Animals
  • CTLA-4 Antigen / metabolism
  • Cell Line, Tumor
  • Cesium Radioisotopes
  • Disease Models, Animal
  • Female
  • Immunity
  • Immunotherapy*
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / radiotherapy*
  • Mice, Inbred C57BL
  • Newcastle disease virus / metabolism*
  • Oncolytic Virotherapy*
  • Oncolytic Viruses / metabolism*
  • Programmed Cell Death 1 Receptor / metabolism

Substances

  • CTLA-4 Antigen
  • Cesium Radioisotopes
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Cesium-137