Understanding IDH mutant gliomas

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IDH-mutant gliomas are unique phenotypically, genetically and epigenetically. Most IDH-mutant gliomas are lower-grade gliomas (LGG) with a more indolent disease process and an overall better prognosis than those with wild-type IDH. However, almost all of them transform to a higher-grade glioma (HGG). Currently, there are no treatments to delay or prevent this transformation, largely due to the lack of understanding of how, why, and when this higher-grade transformation (HT) occurs during the course of the disease. An increased number of somatic mutations are accumulated when LGGs transform to a higher grade in IDH-mutant gliomas, leading to a rapid tumor progression. A subset of these transformed tumors develops a very high number of mutations, a phenomenon referred to as the hypermutator phenotype (HMP), and no longer responds to the currently available therapies. This well-established clinical phenomenon is not well-understood partly due to the lack of adequate preclinical models. We developed a clinical trial to allow the longitudinal monitoring of the level of 2-HG, the ratio of lactate/pyruvate in IDH-mutated gliomas by using proton magnetic resonance spectroscopy (1H-MRS) and hyperpolarized 13Cpyruvate MRS imaging (HP 13C Pyruvate MRSI) approaches. The protocol will include sampling the tumor tissue at the time of clinical disease progression and/or imaging signal change. This part of the study enables potential non-invasive early detection of HT and tissue acquisition that allows us to interrogate the molecular and metabolic mechanisms of HT/HMP. The selection of tumors with HMP will further empower another clinical trial to evaluate an immune checkpoint inhibitor (ICPI) treatment in IDH mutant gliomas. The second part of the study is to determine whether tumor mutation burden correlates with the response to CPI in IDH-mutant gliomas. To address this specific aim, a Phase II clinical trial will compare the efficacy of ICPI therapy, using an anti-PD-1 antibody, nivolumab, between IDH-mutant gliomas patients with and without HMP. The primary objective is to measure the progression-free survival rate at 6 months in two cohorts of the patient. Overall survival and PFS at 12 months and overall survival are the secondary endpoints. Neoantigen and tumor-specific mutation loads from the tumor tissues will be correlated with treatment response. Other correlative studies include the evaluation of immune profiles of the tumor microenvironment by immunohistochemistry and RNA sequencing, immune competency of immune cells and cytokine profile in peripheral blood. T cell receptor (TCR) repertoire in tumor and peripheral blood mononuclear cells will be measured as well. Upon completion of the study, we will provide the first prospective evidence to address a long-standing question in the field of neuro-oncology: whether TMB correlates with immune CPI in IDH-mutant gliomas. Additionally, the results of the correlative studies will provide insights into response to immunotherapy in IDH-mutant gliomas.