Abstract
BackgroundGlioblastoma (GBM) is a poorly immunogenic neoplasm treated with focused radiation. Immunotherapy has demonstrated synergistic survival effects with stereotactic radiosurgery (SRS) in murine GBM. GITR is a co-stimulatory molecule expressed...
Highlights
Glioblastoma (GBM) is a poorly immunogenic neoplasm treated with focused radiation
Similar to blockade of checkpoints PD-1 and lymphocyte activating gene (LAG)-3, among others, activation of tumor necrosis factor receptor (TNFR) family checkpoint molecules has not led to severe toxicities in preclinical models, making Glucocorticoid-induced tumor necrosis factor related protein (GITR) an attractive target for future immune checkpoint modulation [18, 19]
GITR activation and stereotactic radiosurgery together produced long-term survivors and tumor regression in murine intracranial GL261 To determine the effectiveness of GITR activation in the setting of adjuvant focal radiation against established GL261-luc murine glioblastoma tumors, an anti-GITR (1) agonist monoclonal antibody (mAb) was dosed according to previous studies of anti-GITR (1) in mouse tumor models and combined with stereotactic radiosurgery (SRS) dosed in a single fraction (Fig. 1a)
Summary
Glioblastoma (GBM) is a poorly immunogenic neoplasm treated with focused radiation. Immunotherapy has demonstrated synergistic survival effects with stereotactic radiosurgery (SRS) in murine GBM. We tested the hypothesis that anti-GITR monoclonal antibody (mAb) and SRS together would confer an immune-mediated survival benefit in glioma using the orthotopic GL261 glioma model. Preclinical studies have demonstrated early successes for the use of immunotherapy against glioma, including antibody-mediated blockade of checkpoints including anti-programmed death-1 (anti-PD-1), anti-cytotoxic T lymphocyte antigen-4 (anti-CTLA-4), and anti-4-1BB, in combination with radiotherapy [5, 6]. Glucocorticoid-induced tumor necrosis factor related protein (GITR) is an immune checkpoint that belongs to the tumor necrosis factor receptor (TNFR) family and is expressed on T lymphocytes, natural killer cells, and granulocytes [7]. Anti-GITR monoclonal antibody (mAb) therapy has resulted in tumor regression in a number of tumor models, but has not yet been tested against murine glioma [12,13,14,15,16,17]. Similar to blockade of checkpoints PD-1 and lymphocyte activating gene (LAG)-3, among others, activation of TNFR family checkpoint molecules has not led to severe toxicities in preclinical models, making GITR an attractive target for future immune checkpoint modulation [18, 19]
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