Journal
CANCER CELL
Volume 32, Issue 2, Pages 253-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2017.07.006
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Funding
- NIH [R01NS032677, R01CA160762]
- Thomas A. Pappas Chair in Neurosciences
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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 G47 Delta expressing murine IL-12 (G47 Delta-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 G47 Delta-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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