Review: Implications of IDH Mutations for Success of Glioma Immunotherapy
- The isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations in glioma are considered ideal therapeutic targets for immunotherapy
- Both therapeutic vaccines and immune checkpoint inhibitors are in early clinical trials for IDH-mutant glioma
- However, IDH-mutant glioma is immunologically quiescent, which may be related to 2-hydroxyglutarate (2HG) production by these tumors. 2HG is an immunosuppressive oncometabolite that works both indirectly and directly to dampen T-cell responses
- Animal and early human studies are underway to explore adding an IDH inhibitor to immunotherapy, in hopes that abrogating 2HG-mediated immune suppression will sensitize the tumor to a vaccine or checkpoint inhibitor
The isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations in glioma are now considered ideal therapeutic targets for immunotherapy. Mutant IDH is an early oncogenic driver and a neoantigen found exclusively and uniformly in gliomas but is not present in normal tissue.
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In Neurosurgical Focus, Massachusetts General Hospital researchers recently reviewed the implications of IDH mutations for immunotherapy of malignant glioma. The authors are Leland G. Richardson, MMSc, MS, of the Translational Brain Tumor Immunology Lab, Bryan D. Choi, MD, PhD, associate director, Center for Brain Tumor Immunology and Immunotherapy in the Department of Neurosurgery and the Pappas Center for Neuro-Oncology, and William T. Curry, MD, co-director of Mass General Neuroscience and director of Neurosurgical Oncology in the Department of Neurosurgery, and colleagues.
The Immune Landscape of IDH-Mutant Glioma
Glioma in general, and especially IDH-mutant glioma, is immunologically "quiet." For example, researchers at Massachusetts General Hospital reported in OncoImmunology that IDH-mutant glioma harbors fewer T cells compared with wild-type tumors. The expression of PD-L1, a target of some immune checkpoint inhibitors, is also substantially reduced.
The distorted immune cell composition of IDH-mutant glioma seems to be driven largely by the accumulation of 2-hydroxyglutarate (2HG), an oncometabolite produced by the mutant IDH enzyme. 2HG has been shown to have critical roles in glioma malignancy transformation, disease progression and therapeutic resistance.
Specifically, 2HG produces both indirect immunosuppression (by preventing recruitment of T cells) and direct immunosuppression (by suppressing T-cell activation and proliferation). Hence, there are questions about how well IDH-mutant glioma will respond to immunotherapy, even though the mutations themselves are theoretically such good targets.
At the time the review was written, three IDH1-specific peptide vaccines were currently being tested in phase 1 clinical trials. Final results from one of these trials have been published in Nature. 33 patients with newly diagnosed IDH1-R132H–positive glioma received eight doses of a vaccine, along with radiation therapy and adjuvant temozolomide, over six months.
The treatment was safe, with no severe treatment-related adverse events. The trial was not powered to demonstrate efficacy, but results demonstrated the vaccine may elicit specific immune responses.
The same group is now recruiting for a randomized phase 1 trial of the same vaccine in combination with avelumab, a checkpoint inhibitor.
Immune Checkpoint Inhibition
The review also lists six phase 2 trials of checkpoint inhibitors in patients with recurrent IDH-mutant glioma. One of them, which evaluated avelumab plus hypofractionated radiation therapy, has been completed but no data have been published.
IDH Inhibitor + Immunotherapy
The FDA has approved ivosidenib, an IDH inhibitor, for certain patients with acute myeloid leukemia or cholangiocarcinoma. The efficacy of this drug and related agents against glioma is unproven.
Given what's now known about 2HG-mediated immunosuppression, the reviewers suggest that rather than pursuing IDH inhibitors as monotherapy for glioma, the field should consider a shift to studying their utility in combination regimens as sensitizing agents for immunotherapy.
Already, preclinical studies have demonstrated success in combining an IDH inhibitor with either vaccination or checkpoint inhibition to treat mice bearing IDH-mutant tumors. In addition, early data from an ongoing phase 1 trial, presented at AACR 2020, suggests the administration of ivosidenib or vorasidenib activates the immune microenvironment in IDH-mutant low-grade glioma.
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