Understanding IDH mutant gliomas

IDH突变型胶质瘤在遗传学和表观遗传学上都是独特的表型。大多数IDH突变的胶质瘤是低级别胶质瘤(LGG)，与野生型IDH相比，其病程更缓慢，预后总体上更好。然而，它们几乎都转化为更高级别的胶质瘤(HGG)。目前，还没有治疗方法来延缓或阻止这种转化，这主要是由于缺乏对疾病过程中如何、为什么以及何时发生这种更高级别的转化(HT)的了解。在IDH突变的胶质瘤中，当LGGs转化为更高级别时，体细胞突变的数量会增加，从而导致肿瘤的快速进展。这些转化的肿瘤中的一部分会产生非常高数量的突变，这种现象被称为超变异体表型(HMP)，不再对目前可用的治疗方法产生反应。这一公认的临床现象尚未得到很好的理解，部分原因是缺乏足够的临床前模型。我们开展了一项临床试验，利用质子磁共振波谱(1H-MRS)和超极化~(13)C丙酮酸MRS成像(HP~(13)C-丙酮酸MRSI)方法对IDH突变胶质瘤的2-HG水平、乳酸/丙酮酸比值进行纵向监测。该方案将包括在临床疾病进展和/或成像信号变化时对肿瘤组织进行采样。该研究的这一部分使我们有可能无创地早期检测甲状旁腺激素和组织获取，从而使我们能够询问甲状旁腺激素/HMP的分子和代谢机制。HMP肿瘤的选择将进一步支持另一项临床试验，以评估免疫检查点抑制剂(ICPI)对IDH突变胶质瘤的治疗。这项研究的第二部分是确定IDH突变胶质瘤的肿瘤突变负荷是否与CPI的反应相关。为了解决这一特定目标，第二阶段临床试验将比较使用抗PD-1抗体nivolumab的ICPI治疗在患有和不患有HMP的IDH突变胶质瘤患者之间的疗效。主要目标是测量两组患者6个月的无进展存活率。总生存期、12个月的PFS和总生存期是次要终点。肿瘤组织中的新抗原和肿瘤特异性突变载量将与治疗反应相关。其他相关研究包括通过免疫组织化学和RNA测序评估肿瘤微环境的免疫谱、免疫细胞的免疫能力和外周血中的细胞因子谱。还将测定肿瘤和外周血单核细胞中的T细胞受体(TCR)谱。在这项研究完成后，我们将提供第一个前瞻性证据来解决神经肿瘤学领域的一个长期存在的问题：在IDH突变的胶质瘤中，TMB是否与免疫CPI相关。此外，相关研究的结果将为IDH突变型胶质瘤的免疫治疗反应提供见解。

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.