IDH-mutated gliomas are unique phenotypically, genetically and epigenetically. Although patients with IDH-mutated gliomas have lower grade gliomas (LGG) with a more indolent disease process and a better prognosis than those with wild-type IDH, 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-mutated 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 respond 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 study to allow the longitudinal monitoring of the level of 2-HG and aerobic glycolysis (ratio of lactate/pyruvate or lactate turnover rate) in IDH-mutated LGGs by using proton magnetic resonance spectroscopy (1H-MRS) and 13C hyperpolarized pyruvate MRS imaging (13C HP Pyruvate MRSI)/13C MRS 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 glioma patients with HMP. The second part of the study is to determine whether tumors with HMP respond better to this immune therapy than those without HMP after disease progression 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 progression-free survival rate at 6 months in two cohorts of the patient. Overall survival and PFS at 12 month 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 including 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. If the study hypothesis is confirmed, an innovative and effective therapy will be established for patients with IDH-mutant glioma that has developed a hypermutator phenotype.
| Lu, Yanxin; Kwintkiewicz, Jakub; Liu, Yang et al. (2017) Chemosensitivity of IDH1-Mutated Gliomas Due to an Impairment in PARP1-Mediated DNA Repair. Cancer Res 77:1709-1718 |
