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

Dipongkor Saha; Robert L Martuza; Samuel D Rabkin

doi:10.1016/j.ccell.2017.07.006

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

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

Authors

Dipongkor Saha¹, Robert L Martuza¹, Samuel D Rabkin²

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Monoclonal / therapeutic use*
B7-H1 Antigen / antagonists & inhibitors
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / metabolism
CD4-Positive T-Lymphocytes / pathology
CD8-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / metabolism
CD8-Positive T-Lymphocytes / pathology
CTLA-4 Antigen / antagonists & inhibitors*
Cell Cycle Checkpoints / drug effects
Combined Modality Therapy
Disease Models, Animal
Female
Glioblastoma / immunology
Glioblastoma / therapy*
Humans
Immunotherapy*
Interleukin-12 / genetics*
Macrophage Activation
Macrophages / immunology*
Macrophages / metabolism
Macrophages / pathology
Mice
Mice, Inbred C57BL
Oncolytic Virotherapy*
Oncolytic Viruses / genetics
Programmed Cell Death 1 Receptor / antagonists & inhibitors*
Tumor Cells, Cultured

Substances

Antibodies, Monoclonal
B7-H1 Antigen
CD274 protein, human
CTLA-4 Antigen
CTLA4 protein, human
PDCD1 protein, human
Programmed Cell Death 1 Receptor
Interleukin-12

Abstract

Publication types

MeSH terms

Substances

Grants and funding