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Stereotactic Adoptive Transfer of Cytotoxic Immune Cells in Murine Models of Orthotopic Human Glioblastoma Multiforme Xenografts
Published on: September 1, 2018
Glioblastoma Eradication Following Immune Checkpoint Blockade in an Orthotopic, Immunocompetent Model
David A Reardon1, Prafulla C Gokhale2, Sarah R Klein3
1Center 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.
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.
Insights
Immune checkpoint inhibitors like PD-1, PD-L1, and CTLA-4 show promise for glioblastoma. Combination therapy of CTLA-4 and PD-1 achieved 75% cure rates in mice, suggesting potential for durable responses.
Area of Science:
- Immunology
- Neuro-oncology
- Cancer Therapy
Background:
- Immune checkpoint inhibitors (cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and PD-L1) have shown success in various cancers.
- Glioblastoma is a lethal brain tumor with significant immunosuppression, and the efficacy of immune checkpoint blockade is unknown.
- Combinatorial regimens targeting complementary immune checkpoints can enhance therapeutic benefits.
Purpose of the Study:
- To evaluate the antitumor efficacy of murine antibodies targeting CTLA-4, PD-1, PD-L1, and PD-L2 in glioblastoma.
- To assess both single-agent and combinatorial regimens against an orthotopic, immunocompetent murine glioblastoma model.
Main Methods:
- Systematic evaluation of murine antibodies targeting immune checkpoint molecules (CTLA-4, PD-1, PD-L1, PD-L2).
- Administration as single-agent therapy and in combinatorial regimens.
- Testing against an orthotopic, immunocompetent murine glioblastoma model.
Main Results:
- Single-agent anti-PD-1, anti-PD-L1, and anti-CTLA-4 therapies resulted in long-term tumor-free survival in 50%, 20%, and 15% of animals, respectively.
- Combination therapy of anti-CTLA-4 plus anti-PD-1 achieved a 75% cure rate, even in advanced-stage tumors.
- Long-term survivors developed tumor-specific immune memory, resisting rechallenge and showing increased activated CD8+ and NK cells, with decreased suppressive immune cells.
Conclusions:
- Immune checkpoint blockade demonstrates significant antitumor efficacy in a murine glioblastoma model.
- Combination therapy of CTLA-4 and PD-1 blockade is highly effective, inducing durable, tumor-specific immune memory.
- Clinical evaluation of PD-1, PD-L1, and CTLA-4 targeted therapies, alone and in combination, is warranted for glioblastoma patients.
