Modifying the Cancer-Immune Set Point Using Vaccinia Virus Expressing Re-Designed interleukin-2

Nat Commun. 2018 Nov 8;9(1):4682. doi: 10.1038/s41467-018-06954-z.

Abstract

The complex immune tumour microenvironment requires an equally complex immunotherapy approach, especially when the cancer-immune set point is non-inflamed. Oncolytic viruses expressing immune activating cytokines might optimally modify the immune microenvironment and improve the antitumour effects. In this study, we have explored a variety of IL-2 constructs expressed by a tumour-selective oncolytic vaccinia virus, designed to maintain IL-2 in the tumour microenvironment to reduce systemic toxicity. An IL-2 construct combining a glycosylphosphatidylinositol (GPI) anchor with a rigid peptide linker leads to functional IL-2 expression on the tumour cell surface and in the tumour microenvironment. This virus construct effectively modifies the cancer-immune set point and treats a variety of murine tumour models with no toxic side effects. In combination with PD-1/PD-L1 blockade this virus cures most of the mice with a high tumour burden. This combination represents a treatment for cancers which are to date unresponsive to immunotherapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Female
  • Immunotherapy
  • Interleukin-2 / metabolism*
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neoplasms / immunology*
  • Neoplasms / pathology
  • Protein Binding / drug effects
  • Tumor Microenvironment / drug effects
  • Vaccinia virus / metabolism*

Substances

  • Antineoplastic Agents
  • Interleukin-2