Skip to main content
Download PDF

Volume 3 Supplement 2

30th Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2015)

  • Poster presentation
  • Open access
  • Published:

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

Journal for ImmunoTherapy of Cancer volume 3, Article number: P194 (2015) Cite this article

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

Figure 1

Author information

Authors and Affiliations

  1. Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Mira Patel & Drew Pardoll

  2. The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Jennifer Kim & Debebe Theodros

  3. The Johns Hopkins University Department of Neurosurgery, Baltimore, MD, USA

    Christopher Jackson, Betty Tyler, Xiaobu Ye, Henry Brem & Michael Lim

  4. The Johns Hopkins University Department of Immunology, Baltimore, MD, USA

    Ada Tam

  5. The Johns Hopkins University Department of Radiation Oncology, Baltimore, MD, USA

    Esteban Velarde

  6. Bristol-Myers Squibb, Baltimore, MD, USA

    Mark Selby

  7. The Johns Hopkins University Departments of Oncology and Cancer Immunology, Baltimore, MD, USA

    Charles Drake

Authors
  1. Mira Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jennifer Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Debebe Theodros
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christopher Jackson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ada Tam
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Esteban Velarde
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Betty Tyler
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiaobu Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Henry Brem
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mark Selby
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Charles Drake
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Drew Pardoll
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Michael Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Patel, M., Kim, J., Theodros, D. et al. Agonist anti-GITR monoclonal antibody and stereotactic radiation induce immune-mediated survival advantage in murine intracranial glioma. j. immunotherapy cancer 3 (Suppl 2), P194 (2015). https://doi.org/10.1186/2051-1426-3-S2-P194

Download citation

  • Published:

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

Keywords