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

Citations Over TimeTop 1% of 2015 papers

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.

Related Papers

• → Inhibiting Immune Checkpoints for the Treatment of Bladder Cancer(2016)34 cited
• → Eradicating micrometastases with immune checkpoint blockade: Strike while the iron is hot(2021)30 cited
• → A progressive T cell exhaustion program mapped across tissues in patients with lung cancer on immune checkpoint blockade(2023)4 cited
• → γδ T cells as unconventional targets of checkpoint blockade(2024)1 cited
• → Distinct immunologic changes in vivo following combination versus individual PD-1 or CTLA-4 checkpoint blockade in human cancer(2014)