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  • Anti-GITR Antibody and Stereotactic Radiation Induces Immune-mediated Prolongation of Survival in Murine Intracranial Glioma

    Final Number:
    790

    Authors:
    Mira A Patel BA; Jennifer E Kim BS; Debebe Theodros BS; Christopher Mitchell Jackson MD; Esteban BS Velarde; Betty Tyler BA; Mark Selby; Xiaobu Ye; Henry Brem MD; Drew Pardoll; Michael Lim MD

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2015 Annual Meeting

    Introduction: The most common primary brain tumor in adults, Glioblastoma (GBM) is a poorly immunogenic neoplasm treated with local radiation. Despite the current standard of care for GBM, median survival remains low. Immunotherapy has demonstrated synergism with stereotactic radiosurgery (SRS) in murine GBM, as radiation promotes a pro-inflammatory tumor microenvironment amenable to the anti-tumor effects of immune cell modulation. Glucocorticoid-induced tumor necrosis factor receptor (GITR) is a co-stimulatory surface receptor expressed constitutively on regulatory T cells and after activation of effector T cells. We tested the hypothesis that non-depleting anti-GITR monoclonal antibody (mAb) and SRS combination therapy would confer immune-mediated survival benefit in murine glioma.

    Methods: Our model was a GL261 mouse glioma cell line transfected with luciferase. Mice were implanted with GL261 and began SRS and anti-GITR treatment after 10 days. Mice were randomized to four treatment groups: (1) control; (2) SRS only; (3) anti-GITR only; (4) anti-GITR+SRS. SRS was delivered to the tumor in one fraction of 10 Gy, and mice were treated with mAb thrice i.p. Mice were euthanized on day 21 to analyze the immunologic profile of brain tumor, spleen, and tumor draining lymph nodes.

    Results: Anti-GITR mAb and SRS conferred significantly improved survival over either treatment alone (p<.01) with a median survival of 31 days. Median survival was 23 days in the control arm, 28 in the anti-GITR only arm and 28 days in the SRS only arm. 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-/IFN-g+) relative to Treg infiltration (CD4+/Foxp3+) at day 21 in mice treated with anti-GITR mAb and SRS.

    Conclusions: Anti-GITR mAb and SRS significantly prolongs survival in murine orthotopic glioma. These findings provide preclinical evidence for the use of anti-GITR non-depleting antibodies alongside SRS in human GBM.

    Patient Care: Our findings provide pre-clinical support for the introduction of anti-GITR monoclonal antibody therapy alongside stereotactic radiation in clinics for the treatment of glioblastoma.

    Learning Objectives: By the conclusion of this session, participants should be able to: 1) identify the synergistic survival benefit of anti-GITR plus SRS combination therapy, 2) recognize the importance of CD4+ T-cells as key mediators of this survival improvement, and 3) understand the role of increased intratumoral CD4+ effector T-cells relative to regulatory T-cells in this treatment mechanism.

    References: 1. Zeng J, See AP, Phallen J, Jackson CM, Belcaid Z, Ruzevick J, Durham N, Meyer C, Harris T, Alebsiano E, Pradilla G, Ford E, Wong J, Hammer H, Mathios D, Tyler B, Brem H, Tran PT, Pardoll DM, Drake CG, Lim M. Anti-PD-1 Blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Rad Onc Bio 2013;86:343–349. 2. Cohen AD, Diab A, Perales MA, Wolchok JD, Rizzuto G, Merghoub T, Huggins D, Liu C, Turk MJ, Restifo NP, Sakaguchi S, Houghton AN. Agonist anti-GITR antibody enhances vaccine-induced CD8(+) T-cell responses and tumor immunity. Cancer Res. 2006 May 1;66(9):4904-12.

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