In adults, glioblastoma multiforme (GBM) is the most common and aggressive form of brain tumor with a median survival of 14.6 months post-diagnosis. Indoleamine 2,3 dioxygenase 1 (IDO1) is an immunosuppressive enzyme that mediates the inhibition of antitumor immunity in a mouse GBM model. Paradoxically, a recent immunohistochemical study found that IDO1 protein is only detectable in 8% of all GBM tumors. Coincidently, human GBM cell lines do not express IDO1, in vitro, while the addition of interferon-gamma (IFN), a proinflammatory cytokine expressed by effector T cells, results in a rapid induction of IDO1 expression and enzymatic activity. In vivo, my laboratory has explored the potential for radiotherapy and/or immune checkpoint blockade to promote the inflammation of brain tumors with a hypothesis that this treatment facilitates protein expression and targetability of IDO1. Supporting this notion, we recently found that the combinatorial treatment of radiotherapy, PD-1 mAb and a highly potent IDO1 inhibitor (IDO1i) synergistically increases the survival of immunocompetent mice bearing intracranial mouse GBM. However, it is unknown whether this strategy is equally beneficial to human GBM. To explore this, we will create and test humanized immunocompetent mouse models bearing HLA-matched GBM for the study of human-specific immunotherapy, while collaborating with our clinical partners to determine IDO1 expression post-radiotherapy/PD-1 blockade in GBM patients. These studies will be performed within the Northwestern University Brain Tumor Institute, which brings together the expertise of neurosurgeons, neuro-oncologists, neuropathologists and basic scientists that focus on the rapid translation of bench discoveries into clinically-beneficial therapeutics.
|Effective start/end date||7/1/16 → 6/30/18|
- Cancer Research Institute (Award Letter 6/22/16)
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