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Cancer Cell. 2017 Aug 14;32(2):253-267.e5. doi: 10.1016/j.ccell.2017.07.006.

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

Author information

1
Molecular Neurosurgery Laboratory and the Brain Tumor Research Center, Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA; Department of Neurosurgery, Harvard Medical School, Boston, MA, USA.
2
Molecular Neurosurgery Laboratory and the Brain Tumor Research Center, Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA; Department of Neurosurgery, Harvard Medical School, Boston, MA, USA. Electronic address: rabkin@mgh.harvard.edu.

Abstract

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.

KEYWORDS:

HSV; cancer stem cells; glioma; immunotherapy; oncolytic virus

PMID:
28810147
PMCID:
PMC5568814
DOI:
10.1016/j.ccell.2017.07.006
[Indexed for MEDLINE]
Free PMC Article

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