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Cancer Immunol Res. 2016 Feb;4(2):124-35. doi: 10.1158/2326-6066.CIR-15-0151. Epub 2015 Nov 6.

Glioblastoma Eradication Following Immune Checkpoint Blockade in an Orthotopic, Immunocompetent Model.

Author information

1
Center for Neuro-Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts. Department of Medical Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts. david_reardon@dfci.harvard.edu.
2
Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts. Lurie Family Imaging Center, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts.
3
Department of Medical Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts.
4
Department of Medical Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts. Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts.
5
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
6
Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts.
7
Lurie Family Imaging Center, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts.
8
Center for Neuro-Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts.
9
Lurie Family Imaging Center, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts. Department of Imaging, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts.
10
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts.

Abstract

Inhibition of immune checkpoints, including cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and its ligand PD-L1, has demonstrated exciting and durable remissions across a spectrum of malignancies. Combinatorial regimens blocking complementary immune checkpoints further enhance the therapeutic benefit. The activity of these agents for patients with glioblastoma, a generally lethal primary brain tumor associated with significant systemic and microenvironmental immunosuppression, is not known. We therefore systematically evaluated the antitumor efficacy of murine antibodies targeting a broad panel of immune checkpoint molecules, including CTLA-4, PD-1, PD-L1, and PD-L2 when administered as single-agent therapy and in combinatorial regimens against an orthotopic, immunocompetent murine glioblastoma model. In these experiments, we observed long-term tumor-free survival following single-agent anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapy in 50%, 20%, and 15% of treated animals, respectively. Combination therapy of anti-CTLA-4 plus anti-PD-1 cured 75% of the animals, even against advanced, later-stage tumors. In long-term survivors, tumor growth was not seen upon intracranial tumor rechallenge, suggesting that tumor-specific immune memory responses were generated. Inhibitory immune checkpoint blockade quantitatively increased activated CD8(+) and natural killer cells and decreased suppressive immune cells in the tumor microenvironment and draining cervical lymph nodes. Our results support prioritizing the clinical evaluation of PD-1, PD-L1, and CTLA-4 single-agent targeted therapy as well as combination therapy of CTLA-4 plus PD-1 blockade for patients with glioblastoma.

PMID:
26546453
DOI:
10.1158/2326-6066.CIR-15-0151
[Indexed for MEDLINE]
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