Immunostimulatory bacterial antigen–armed oncolytic measles virotherapy significantly increases the potency of anti-PD1 checkpoint therapy
Eleni Panagioti, … , Ianko D. Iankov, Evanthia Galanis
Eleni Panagioti, … , Ianko D. Iankov, Evanthia Galanis
Published July 1, 2021
Citation Information: J Clin Invest. 2021;131(13):e141614. https://doi.org/10.1172/JCI141614.
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Research Article Oncology

Immunostimulatory bacterial antigen–armed oncolytic measles virotherapy significantly increases the potency of anti-PD1 checkpoint therapy

Abstract

Clinical immunotherapy approaches are lacking efficacy in the treatment of glioblastoma (GBM). In this study, we sought to reverse local and systemic GBM-induced immunosuppression using the Helicobacter pylori neutrophil-activating protein (NAP), a potent TLR2 agonist, as an immunostimulatory transgene expressed in an oncolytic measles virus (MV) platform, retargeted to allow viral entry through the urokinase-type plasminogen activator receptor (uPAR). While single-agent murine anti-PD1 treatment or repeat in situ immunization with MV-s-NAP-uPA provided modest survival benefit in MV-resistant syngeneic GBM models, the combination treatment led to synergy with a cure rate of 80% in mice bearing intracranial GL261 tumors and 72% in mice with CT-2A tumors. Combination NAP-immunovirotherapy induced massive influx of lymphoid cells in mouse brain, with CD8+ T cell predominance; therapeutic efficacy was CD8+ T cell dependent. Inhibition of the IFN response pathway using the JAK1/JAK2 inhibitor ruxolitinib decreased PD-L1 expression on myeloid-derived suppressor cells in the brain and further potentiated the therapeutic effect of MV-s-NAP-uPA and anti-PD1. Our findings support the notion that MV strains armed with bacterial immunostimulatory antigens represent an effective strategy to overcome the limited efficacy of immune checkpoint inhibitor–based therapies in GBM, creating a promising translational strategy for this lethal brain tumor.

Authors

Eleni Panagioti, Cheyne Kurokawa, Kimberly Viker, Arun Ammayappan, S. Keith Anderson, Sotiris Sotiriou, Kyriakos Chatzopoulos, Katayoun Ayasoufi, Aaron J. Johnson, Ianko D. Iankov, Evanthia Galanis

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Figure 5

MV-s-NAP-uPA in combination with anti-PD1 results in synergistic therapeutic efficacy against glioblastoma.

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MV-s-NAP-uPA in combination with anti-PD1 results in synergistic therape...
(A) Survival outcomes in athymic nude mice implanted orthotopically with GBM6 or GBM12 cells and treated with intratumoral administration of MV-s-NAP-uPA or heat-inactivated MV-s-NAP-uPA (2 × 105 TCID50) once every 3 days for a total of 5 or 3 doses, respectively (n = 6 mice per group). (B) Survival outcomes of C57BL/6 mice bearing CT-2A glioma following treatment with uPAR-retargeted MV strains in combination with anti-PD1. Mouse anti-PD1 or isotype control was administered i.p. at 200 μg/mouse for a total of 5 doses as per the depicted treatment schema. Inactivated MV-s-NAP-uPA virus was used as control (n = 11–12 mice per group). (C) Long-term-surviving CT-2A animals were rechallenged on day 180 with homologous CT-2A tumor cells or heterologous B16-F10 melanoma cells in the hemisphere contralateral to the primary injected tumor and survival was monitored (n = 3–4 mice per group). (D) Survival outcomes of C57BL/6 mice bearing GL261 glioma following treatment with uPAR-retargeted MV strains and anti-PD1 (n = 6–7 mice per group). The experiment was repeated twice with similar outcomes. (E) Long-term-surviving GL261 mice were challenged on day 180 with homologous GL261 tumor cells or heterologous B16-F10 melanoma cells in the hemisphere contralateral to the primary implanted tumor and overall survival was monitored. Kaplan-Meier survival curves and P values that were determined using the log-rank Mantel-Cox test and Benjamini and Hochberg adjustment for multiple comparisons. *P < 0.05; **P < 0.01; ***P < 0.001. NS, not significant. Detailed statistical differences between groups are presented in Tables 1 and 2.