Immunovirotherapy with vesicular stomatitis virus and PD-L1 blockade enhances therapeutic outcome in murine acute myeloid leukemia

Blood. 2016 Mar 17;127(11):1449-58. doi: 10.1182/blood-2015-06-652503. Epub 2015 Dec 28.


Patients with relapsed acute myeloid leukemia (AML) have limited therapeutic options. Vesicular stomatitis virus (VSV)-interferon β (IFNβ)-sodium iodide symporter (NIS) is an oncolytic VSV encoding IFNβ and the NIS reporter. Syngeneic AML C1498 tumors responded to IV therapy with VSV-murine IFNβ (mIFNβ)-NIS in a dose-dependent manner. Imaging for NIS expression showed robust virus infection within the tumors. Virus infection did not increase programmed death ligand 1 (PD-L1) on tumor cells. Combining VSV-mIFNβ-NIS with anti-PD-L1 antibody (Ab) therapy enhanced antitumor activity compared with treatment with virus alone or Ab alone; this enhancement was not significant at higher VSV-mIFNβ-NIS doses. Systemic VSV therapy reduced systemic C1498-green fluorescent protein (GFP) tumor burden in the blood, bone marrow, spleen, and liver of mice with AML. Combination VSV-mIFNβ-NIS and anti-PD-L1 Ab therapy significantly enhanced the survival of these mice with no evidence of toxicity, compared with isotype control, anti-PD-L1, or virus alone. There was an increase in tumor-infiltrating CD4 and CD8 cells. Single-agent VSV-mIFNβ-NIS virotherapy induced both VSV-specific and GFP-specific CD8 T cells as determined by IFN-γ enzyme-linked immunospot, pentamer, and intracellular IFN-γ staining assays. Both of these responses were further enhanced by addition of anti-PD-L1 Ab. Depletion of CD8 or natural killer cells, but not CD4 cells, resulted in loss of antitumor activity in the VSV/anti-PD-L1 group. Clinical samples from chronic myelomonocytic leukemia and acute myelomonocytic leukemia appear to be especially susceptible to VSV. Overall, our studies show that oncolytic virotherapy combined with immune checkpoint blockade is a promising approach to AML therapy.

Publication types

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

MeSH terms

  • Animals
  • B7-H1 Antigen / analysis
  • B7-H1 Antigen / immunology*
  • Bone Marrow / pathology
  • Cell Line, Tumor
  • Combined Modality Therapy
  • Female
  • Genes, Reporter
  • Genetic Vectors / genetics
  • Green Fluorescent Proteins / genetics
  • Humans
  • Immunotherapy*
  • Interferon-beta / genetics
  • Lentivirus / genetics
  • Leukemia, Myeloid, Acute / diagnostic imaging
  • Leukemia, Myeloid, Acute / therapy*
  • Leukemia, Myelomonocytic, Acute / pathology
  • Leukemia, Myelomonocytic, Chronic / pathology
  • Leukocytes, Mononuclear / pathology
  • Lymphocyte Subsets / immunology
  • Lymphocytes, Tumor-Infiltrating / chemistry
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Proteins / analysis
  • Oncolytic Virotherapy*
  • Radionuclide Imaging
  • Symporters / genetics
  • Tumor Burden
  • Vesicular stomatitis Indiana virus / physiology*


  • B7-H1 Antigen
  • CD274 protein, human
  • Cd274 protein, mouse
  • Neoplasm Proteins
  • Symporters
  • Green Fluorescent Proteins
  • sodium-iodide symporter
  • Interferon-beta