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  • Open Access

Agonist anti-GITR monoclonal antibody and stereotactic radiation induce immune-mediated survival advantage in murine intracranial glioma

  • 1,
  • 2,
  • 2,
  • 3,
  • 4,
  • 5,
  • 3,
  • 3,
  • 3,
  • 6,
  • 7,
  • 1 and
  • 3
Journal for ImmunoTherapy of Cancer20153 (Suppl 2) :P194

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

  • Published:

Keywords

  • Tumor Drain Lymph Node
  • Intracranial Glioma
  • Treg Infiltration
  • IgG1 Treatment
  • Murine Glioma

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 1

Authors’ Affiliations

(1)
Johns Hopkins University School of Medicine, Baltimore, MD, USA
(2)
The Johns Hopkins University School of Medicine, Baltimore, MD, USA
(3)
The Johns Hopkins University Department of Neurosurgery, Baltimore, MD, USA
(4)
The Johns Hopkins University Department of Immunology, Baltimore, MD, USA
(5)
The Johns Hopkins University Department of Radiation Oncology, Baltimore, MD, USA
(6)
Bristol-Myers Squibb, Baltimore, MD, USA
(7)
The Johns Hopkins University Departments of Oncology and Cancer Immunology, Baltimore, MD, USA

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