Therapeutic Efficacy of an Oncolytic Influenza Virus Carrying an Antibody Against Programmed Cell Death 1 in Hepatocellular Carcinoma

Hum Gene Ther. 2022 Mar;33(5-6):309-317. doi: 10.1089/hum.2021.167. Epub 2022 Feb 23.

Abstract

Oncolytic virus therapy is a promising novel immunotherapy. In this report, we engineered a novel oncolytic influenza virus (IV) carrying an antihuman programmed cell death 1 (PD-1) monoclonal antibody utilizing reverse genetics. A reassortant chimeric IV, named rFlu-huPD1, was synthesized as follows: the heavy chain of the PD-1 antibody was encoded on the PB1 fragment, and the light chain of the PD-1 antibody was encoded on the polymerase acid protein fragment. rFlu-huPD1 antibodies were produced in infected ovalantoic eggs and could replicate to high titers. Moreover, selective cytotoxicity of rFlu-huPD1 was upregulated in multiple hepatocellular carcinoma (HCC) cell lines compared with a control, as determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Furthermore, the activation of T cells in the spleen of tumor-bearing BALB/c mice treated with rFlu-huPD1 was observed, especially cytotoxic CD8+ T cell activation in vivo. In addition, in a patient-derived xenograft liver cancer mouse model, tumor growth was reduced and the overall survival of the mice was increased by intratumoral injections with rFlu-huPD1 compared with wild-type PR8 virus. Taken together, these findings provide evidence for the utility of a combination of oncolytic IVs expressing PD-1 inhibitors for use in HCC virotherapy.

Keywords: PD-1; hepatocellular carcinoma; immune checkpoint blockade; oncolytic influenza virus; rFlu-huPD1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / therapeutic use
  • Apoptosis
  • Carcinoma, Hepatocellular* / genetics
  • Carcinoma, Hepatocellular* / pathology
  • Carcinoma, Hepatocellular* / therapy
  • Cell Line, Tumor
  • Disease Models, Animal
  • Humans
  • Liver Neoplasms* / genetics
  • Liver Neoplasms* / pathology
  • Liver Neoplasms* / therapy
  • Mice
  • Oncolytic Virotherapy*
  • Oncolytic Viruses* / genetics
  • Orthomyxoviridae*
  • Programmed Cell Death 1 Receptor / genetics

Substances

  • Antibodies, Monoclonal
  • Programmed Cell Death 1 Receptor