Immunovirotherapy with measles virus strains in combination with anti-PD-1 antibody blockade enhances antitumor activity in glioblastoma treatment.
Glioblastoma (GBM) is the most common primary malignant brain tumor and has a dismal prognosis. Measles virus (MV) therapy of GBM is a promising strategy due to preclinical efficacy, excellent clinical safety, and its ability to evoke antitumor pro-inflammatory responses. We hypothesized that combining anti- programmed cell death protein 1 (anti-PD-1) blockade and MV therapy can overcome immunosuppression and enhance immune effector cell responses against GBM, thus improving therapeutic outcome.



In vitro assays of MV infection of glioma cells and infected glioma cells with mouse microglia ± aPD-1 blockade were established to assess damage associated molecular pattern (DAMP) molecule production, migration, and pro-inflammatory effects. C57BL/6 or athymic mice bearing syngeneic orthotopic GL261 gliomas were treated with MV, aPD-1, and combination treatment. T2* weighted immune cell-specific MRI and fluorescence activated cell sorting (FACS) analysis of treated mouse brains was used to examine adaptive immune responses following therapy.



In vitro, MV infection induced human GBM cell secretion of DAMP (high-mobility group protein 1, heat shock protein 90) and upregulated programmed cell death ligand 1 (PD-L1). MV infection of GL261 murine glioma cells resulted in a pro-inflammatory response and increased migration of BV2 microglia. In vivo, MV+aPD-1 therapy synergistically enhanced survival of C57BL/6 mice bearing syngeneic orthotopic GL261 gliomas. MRI showed increased inflammatory cell influx into the brains of mice treated with MV+aPD-1; FACS analysis confirmed increased T-cell influx predominantly consisting of activated CD8+ T cells.



This report demonstrates that oncolytic measles virotherapy in combination with aPD-1 blockade significantly improves survival outcome in a syngeneic GBM model and supports the potential of clinical/translational strategies combining MV with αPD-1 therapy in GBM treatment.
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.|Oncology, Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA.
Jayson
J
Hardcastle
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Lisa
L
Mills
Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA.
Courtney S
CS
Malo
Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA.
Fang
F
Jin
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.|Mayo Clinic Graduate School, Mayo Clinic, Rochester, Minnesota, USA.
Cheyne
C
Kurokawa
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.|Oncology, Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA.
Hirosha
H
Geekiyanage
Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA.
Mark
M
Schroeder
Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA.
Jann
J
Sarkaria
Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA.|Department of Neurology Mayo Clinic, Rochester, Minnesota, USA.
Aaron J
AJ
Johnson
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.|Oncology, Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA.
Evanthia
E
Galanis
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D060890:B7-H1 Antigen / Q000378:metabolism; D001932:Brain Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy* / Q000662:veterinary; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005909:Glioblastoma / Q000276:immunology / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D024243:HMGB1 Protein / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy; D008459:Measles virus / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D050130:Oncolytic Virotherapy; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000276:immunology*; D016019:Survival Analysis
D000906:Antibodies; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D024243:HMGB1 Protein; D018841:HSP90 Heat-Shock Proteins; D061026:Programmed Cell Death 1 Receptor
aPD-1; glioblastoma; immunovirotherapy; measles virus
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