Macrophage Polarization Contributes to Glioblastoma Eradication by Combination Immunovirotherapy and Immune Checkpoint Blockade

Publication date: 14 August 2017
Source:Cancer Cell, Volume 32, Issue 2
Author(s): Dipongkor Saha, Robert L. Martuza, Samuel D. Rabkin
Glioblastoma is an immunosuppressive, fatal brain cancer that contains glioblastoma stem-like cells (GSCs). Oncolytic herpes simplex virus (oHSV) selectively replicates in cancer cells while inducing anti-tumor immunity. oHSV G47Δ expressing murine IL-12 (G47Δ-mIL12), antibodies to immune checkpoints (CTLA-4, PD-1, PD-L1), or dual combinations modestly extended survival of a mouse glioma model. However, the triple combination of anti-CTLA-4, anti-PD-1, and G47Δ-mIL12 cured most mice in two glioma models. This treatment was associated with macrophage influx and M1-like polarization, along with increased T effector to T regulatory cell ratios. Immune cell depletion studies demonstrated that CD4⁺ and CD8⁺ T cells as well as macrophages are required for synergistic curative activity. This combination should be translatable to the clinic and other immunosuppressive cancers.

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Saha et al. show that the combination of an oncolytic virus expressing IL-12 with two immune checkpoint inhibitors, anti-CTLA-4 and anti-PD1 antibodies, can eradicate glioma in two mouse models. The therapeutic efficacy of the combination treatment depends on CD4⁺ and CD8⁺ T cells as well as macrophages.


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