title: Immunovirotherapy with vesicular stomatitis virus and PD-L1 blockade enhances therapeutic outcome in murine acute myeloid leukemia.
abstract: 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.
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, MN; Pathology Center, Shanghai General Hospital Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China; and.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Shen
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, MN.
authors.forename: Mrinal M
authors.initials: MM
authors.lastname: Patnaik
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, MN;
authors.forename: Autumn
authors.initials: A
authors.lastname: Ruiz
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, MN; Division of Hematology, Mayo Clinic, Rochester, MN.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Russell
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, MN;
authors.forename: Kah-Whye
authors.initials: KW
authors.lastname: Peng
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000032:analysis / Q000276:immunology*; D001853:Bone Marrow / Q000473:pathology; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005260:Female; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007167:Immunotherapy; D016899:Interferon-beta / Q000235:genetics; D016086:Lentivirus / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000000981:diagnostic imaging / Q000628:therapy*; D015479:Leukemia, Myelomonocytic, Acute / Q000473:pathology; D015477:Leukemia, Myelomonocytic, Chronic / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000473:pathology; D016131:Lymphocyte Subsets / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000737:chemistry / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000032:analysis; D050130:Oncolytic Virotherapy; D011877:Radionuclide Imaging; D027981:Symporters / Q000235:genetics; D047368:Tumor Burden; D014721:Vesicular stomatitis Indiana virus / Q000502:physiology*; D000099209:Sodium-Iodide Symporters
chemical_list: D060890:B7-H1 Antigen; D049452:Green Fluorescent Proteins; D016899:Interferon-beta; D009363:Neoplasm Proteins; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C423236:CD274 protein, human; C498919:Cd274 protein, mouse