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 6

Intratumoral MV-s-NAP-uPA and systemic anti-PD1 immunovirotherapy results in potent cellular immune response against glioblastoma.

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Intratumoral MV-s-NAP-uPA and systemic anti-PD1 immunovirotherapy result...
Mice bearing (A) CT-2A and (B) GL261 orthotopic tumors were treated according to the schema in Figure 5, B and D, respectively. At the time point that at least 2 mice from the vehicle plus isotype control group exhibited clinical symptoms of GBM disease progression, all groups of mice were sacrificed for analysis of immune cell responses in the brain. Mice were perfused and brains were processed for immunophenotyping. Graph values represent mean ± SD (n = 4–5 mice per group). (C) Mice bearing CT-2A brain tumors were treated with MV-s-NAP-uPA and anti-PD1 antibody as described in Figure 5B in the presence of anti-CD4, -CD8, -CD4 plus -CD8, -NK1.1, and -Ly6G cell-depleting antibodies. Kaplan-Meier survival curves and Benjamini and Hochberg adjustment for multiple comparisons were used to calculate median survival times (n = 8–10 mice per group). (D) Images of spleen and thymus sizes harvested from individual mice after completion of the MV-s-NAP-uPA and/or anti-PD1 treatment of the GL261 glioblastoma model. Untreated naive mice and naive mice injected with saline (vehicle) intracranially were included in the experiment as controls. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 by 2-way ANOVA followed by Tukey’s multiple comparison test. NS, not significant.