Understanding IDH mutant gliomas

IDH突变型胶质瘤在表型、遗传和表观遗传上是独特的。最 IDH突变型胶质瘤是低级别胶质瘤（LGG），具有更惰性的疾病过程， 总体预后优于野生型IDH患者。然而，几乎所有的转变 高级别胶质瘤（HGG）。目前，没有治疗方法可以延迟或预防这种情况。 转型，很大程度上是由于缺乏了解如何，为什么，以及何时这一点， 高级别转化（HT）发生在疾病过程中。数量增加 IDH突变型中LGG向更高级别转化时， 神经胶质瘤，导致肿瘤快速进展。这些转化的肿瘤的一个子集发展为 非常高数量的突变，一种被称为超变子表型（HMP）的现象， 并且对现有的治疗不再有反应。这一成熟的临床 这种现象还没有得到很好的理解，部分原因是缺乏足够的临床前模型。我们 开发了一项临床试验，允许纵向监测2-HG的水平， IDH突变胶质瘤中乳酸/丙酮酸比值的质子磁共振研究 波谱（1H-MRS）和13 C超极化丙酮酸盐MRS成像（13 C HP Pyruvate MRSI） 接近。该方案将包括在临床试验时对肿瘤组织进行采样。 疾病进展和/或成像信号变化。这部分研究使潜在的 HT的非侵入性早期检测和组织采集，使我们能够询问 HT/HMP的分子和代谢机制。选择具有HMP的肿瘤将进一步 授权另一项临床试验评估免疫检查点抑制剂（ICPI）治疗， IDH突变型HMP胶质瘤患者。研究的第二部分是确定是否 与HMP的肿瘤更好地响应这种免疫治疗比那些没有HMP的疾病后 IDH突变胶质瘤的进展。为了解决这一具体目标，一项II期临床试验 将比较使用抗PD-1抗体纳武单抗的ICPI治疗在以下两种情况下的疗效： 伴有和不伴有HMP的IDH突变型胶质瘤患者。主要目标是测量 两组患者6个月时的无进展生存率。总生存期和 12个月PFS和总生存期为次要终点。新抗原和 来自肿瘤组织的肿瘤特异性突变负荷将与治疗相关 反应其他相关研究包括评估肿瘤的免疫特征 通过免疫组织化学和RNA测序的微环境;免疫细胞的免疫能力 和外周血中的细胞因子谱。肿瘤中的T细胞受体（TCR）库和 还将测量外周血单核细胞。如果研究假设是 确认，将为患有以下疾病的患者建立一种创新和有效的治疗方法： IDH突变型神经胶质瘤已发展为超变子表型。

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-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 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 13C hyperpolarized pyruvate MRS imaging (13C HP 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 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 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. 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.