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Poster Presentation
Agonist anti-GITR monoclonal antibody and stereotactic radiation induce immune-mediated survival advantage in murine intracranial glioma
  1. Mira Patel1,
  2. Jennifer Kim2,
  3. Debebe Theodros2,
  4. Christopher Jackson3,
  5. Ada Tam4,
  6. Esteban Velarde5,
  7. Betty Tyler3,
  8. Xiaobu Ye3,
  9. Henry Brem3,
  10. Mark Selby6,
  11. Charles Drake7,
  12. Drew Pardoll1 and
  13. Michael Lim3
  1. Aff1 grid.21107.350000000121719311Johns Hopkins University School of Medicine Baltimore MD USA
  2. Aff2 grid.21107.350000000121719311The Johns Hopkins University School of Medicine Baltimore MD USA
  3. Aff3 grid.21107.350000000121719311The Johns Hopkins University Department of Neurosurgery Baltimore MD USA
  4. Aff4 grid.21107.350000000121719311The Johns Hopkins University Department of Immunology Baltimore MD USA
  5. Aff5 grid.21107.350000000121719311The Johns Hopkins University Department of Radiation Oncology Baltimore MD USA
  6. Aff6 grid.419971.3Bristol-Myers Squibb Baltimore MD USA
  7. Aff7 grid.21107.350000000121719311The Johns Hopkins University Departments of Oncology and Cancer Immunology Baltimore MD USA

https://doi.org/10.1186/2051-1426-3-S2-P194

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    Meeting abstracts

    Background

    Glioblastoma (GBM) is a poorly immunogenic neoplasm treated with local radiation. Despite the standard of care, median survival remains low. Immunotherapy has synergized with stereotactic radiosurgery (SRS) in murine GBM, as radiation promotes a pro-inflammatory tumor microenvironment amenable to the anti-tumor effects of immune modulation. Glucocorticoid-induced tumor necrosis factor receptor (GITR) is a co-stimulatory receptor expressed constitutively on regulatory T cells and inducibly on effector T cells. We tested the hypothesis that anti-GITR monoclonal antibody (mAb) and SRS combination therapy would confer immune-mediated survival benefit in murine glioma.

    Methods

    Mice were implanted with GL261-luc murine glioma cells and began SRS and anti-GITR IgG1 treatment after 10 days. Mice were randomized to four treatment groups: control, SRS only, anti-GITR only, anti-GITR+SRS. SRS was delivered to the tumor in one fraction; mice were given mAb thrice i.p. Mice were euthanized on day 21 to analyze the immunologic profile of tumor, spleen, and tumor draining lymph nodes.

    Results

    Anti-GITR mAb plus SRS conferred significantly improved survival over either treatment alone (p < .0001, cure rate 24%). The increased survival required CD4+T cells but not CD8+T cells or regulatory T cells (Tregs). There was elevated intratumoral CD4+ effector-cell infiltration (CD4+/Foxp3-/IFNγ+) relative to Treg infiltration (CD4+/Foxp3+) at day 21 in mice treated with anti-GITR+SRS, and significantly elevated IFNγ and IL-2 production by CD4+T cells and elevated IFNγ and TNFα production by CD8+T cells. Intratumoral mononuclear cells demonstrated increased mRNA expression of pro-inflammatory M1 markers and decreased expression of immunosuppressive M2 markers.

    Conclusions

    In all, anti-GITR mAb synergizes with SRS to significantly prolong survival in murine orthotopic glioma in a potentially CD4+ Th1-dominant anti-tumor mechanism with M1 polarization. These findings provide preclinical evidence for the use of anti-GITR IgG1 non-depleting antibodies alongside SRS in human GBM.

    Figure

    Figure 1