IDO1 in glioblastoma; translating work from mouse to man

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date7/1/166/30/18

Funding

  • Cancer Research Institute (Award Letter 6/22/16)

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