Glioma immunotherapy targeting IDH mutation-derived epitope and immunosuppression

针对 IDH 突变衍生表位和免疫抑制的胶质瘤免疫治疗

• 批准号: 10174862
• 负责人: Hideho Okada
• 金额: $ 36.94万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10174862
• 关键词: 19q; Address; Adoptive Cell Transfers; Affect; Age; Amino Acids; Antigen-Presenting Cells; Antigens; Arginine; Avidity; Binding; Brain Neoplasms; CD4 Positive T Lymphocytes; CD8B1 gene; CXC chemokine receptor 3; CXCL10 gene; Cell physiology; Cells; Cellular immunotherapy; Clinical Trials; Complementary DNA; Cross-Priming; Cytotoxic T-Lymphocytes; DR1 gene; Data; Diagnosis; Diffuse; Disease; Down-Regulation; Enzymes; Epigenetic Process; Epitopes; Exhibits; Exposure to; Foundations; Future; Glioblastoma; Glioma; HLA Antigens; Histidine; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; Human; Immunosuppression; Immunotherapy; Infiltration; Interferons; Isocitrate Dehydrogenase; Lead; Lymphocyte Activation; Modeling; Mus; Mutation; Myeloid Cells; Operative Surgical Procedures; Outcome Study; PPBP gene; Patients; Peptides; Positioning Attribute; Pre-Clinical Model; Process; Production; Proteins; Radiation; Recurrence; Reporting; STAT1 gene; STAT1 protein; Safety; Solid; Specificity; T-Cell Receptor; T-Lymphocyte; Testing; Th1 Cells; Therapeutic; Therapeutic Effect; Transgenic Mice; Tumor-infiltrating immune cells; alpha ketoglutarate; base; chemokine; cytotoxic; cytotoxic CD8 T cells; effector T cell; enantiomer; gain of function; genome-wide; immunotherapy clinical trials; improved; inhibitor/antagonist; insight; mouse model; mutant; neoantigens; novel; phase 1 study; pre-clinical; trafficking; vaccine efficacy

ABSTRACT Mutations of the isocitrate dehydrogenase (IDH) enzymes IDH1 and IDH2 are early and frequent genetic alterations in WHO grade II or III lower grade diffuse gliomas (LGG), as well as in secondary glioblastomas, which progress from LGG. Although IDH mutant (IDH-MUT) LGGs are associated with longer survival compared to IDH wild type (IDH-WT) LGGs, most IDH-MUT LGG patients eventually succumb to the disease. The median age at diagnosis is younger in IDH-MUT patients than IDH-WT patients, suggesting more therapeutic opportunities for IDH-MUT patients, such as immunotherapy. All IDH1 and IDH2 mutations confer a novel gain-of-function activity by converting α-ketoglutarate (αKG) to (R)-enantiomer of 2-hydroxyglutarate (R- 2HG), and coordinate genome-wide epigenetic changes. Approximately 90% of all IDH mutations are a single base mutation at position 132 of IDH1 replacing arginine (R) with histidine (H; R132H). As a way to target the IDH1 (R132H)-derived epitope by immunotherapy, we recently cloned cDNAs for T-cell receptors (TCR) that are specifically reactive to the IDH1(R132H)-derived peptide epitope (IDH1-TCR). Without immunotherapy, LGGs are known to be infiltrated by relatively few T-cells, implying that LGG may exhibit a unique immunosuppression mechanism. To support this, we have recently demonstrated that IDH mutations and R- 2HG lead to decreased effector T-cell-attracting chemokines, such as CXCL10, thereby suppressing infiltration of effector T-cells in gliomas. Our data also show that a mutant IDH1-specific inhibitor recovered CXCL10 and enhanced the efficacy of T-cell-based immunotherapy in preclinical mouse models of IDH-MUT gliomas. Finally, our data indicate that R-2HG also suppresses CXCL10 production by myeloid cells. In the current proposal, we will build on these data to evaluate our central hypothesis that IDH-MUT gliomas could be susceptible to immunotherapy by proper modulation of the LGG microenvironment and targeting of the IDH1(R132H)-derived neoantigen epitope. We will test the following Specific Aims: Aim 1. Determine the effects of IDH mutations on glioma-infiltrating myeloid cells. As myeloid cells could function as antigen-presenting cells (APCs), we will delineate the effects of IDH mutations on glioma-infiltrating myeloid cells and determine whether inhibition of mutant IDH can promote their APC functions. Aim 2. Determine how the IDH(1R132H) epitope is presented and recognized by the IDH1-TCRs. We will determine antigen-specificity and avidity of TCRs reactive to the IDH1(R132H) epitope. We will also evaluate how IDH1-TCRs recognize the epitope presented by a variety of HLA-class II molecules. Aim 3. Determine the efficacy and mechanisms of ACT with IDH1-TCR-Th1 cells in preclinical models. Using HLA-A2.DR1 transgenic mice, we will evaluate two mutually non-exclusive mechanistic hypotheses: 1) Th1-cells function as cytotoxic T lymphocytes (CTLs) and directly kill HLA-class II+ IDH1(R132H)+ glioma cells, and 2) Th1-cells promote cross-priming of CD8+ CTLs, which in turn kill glioma cells.

摘要 异柠檬酸脱氢酶（IDH）酶IDH 1和IDH 2的突变是早期和频繁的遗传突变， WHO II级或III级低级别弥漫性胶质瘤（LGG）以及继发性胶质母细胞瘤的改变， 从LGG发展而来。尽管IDH突变体（IDH-MUT）LGG与更长的生存期相关， 与IDH野生型（IDH-WT）LGG相比，大多数IDH-MUT LGG患者最终死于该疾病。 IDH-MUT患者诊断时的中位年龄比IDH-WT患者更年轻，这表明IDH-MUT患者的中位年龄比IDH-WT患者更小。 IDH-MUT患者的治疗机会，如免疫疗法。所有IDH 1和IDH 2突变都赋予一个 通过将α-酮戊二酸（αKG）转化为2-羟基戊二酸（R-）的（R）-对映体而获得的新的功能获得活性 2 HG），并协调全基因组表观遗传变化。大约90%的IDH突变是单一的。 IDH 1第132位的碱基突变，精氨酸（R）被组氨酸（H; R132 H）取代。作为一种针对 IDH 1（R132 H）衍生的表位，我们最近克隆了T细胞受体（TCR）的cDNA， 与IDH 1（R132 H）衍生的肽表位（IDH 1-TCR）特异性反应。如果没有免疫疗法， 已知LGG被相对较少的T细胞浸润，这意味着LGG可能表现出独特的免疫调节作用。 免疫抑制机制为了支持这一点，我们最近证明IDH突变和R- 2 HG导致效应T细胞吸引趋化因子如CXCL 10减少，从而抑制浸润 神经胶质瘤中的效应T细胞。我们的数据还表明，突变IDH 1特异性抑制剂恢复了CXCL 10， 增强了基于T细胞的免疫疗法在IDH-MUT胶质瘤临床前小鼠模型中的功效。 最后，我们的数据表明，R-2 HG还抑制骨髓细胞产生CXCL 10。在当前 建议，我们将建立在这些数据，以评估我们的中心假设，IDH-MUT胶质瘤可能是 通过适当调节LGG微环境和靶向 IDH 1（R132 H）衍生的新抗原表位。我们将测试以下具体目标： 目标1。确定IDH突变对神经胶质瘤浸润髓样细胞的影响。就像骨髓细胞 作为抗原呈递细胞（APC），我们将描述IDH突变对胶质瘤浸润的影响。 髓样细胞，并确定抑制突变IDH是否可以促进其APC功能。 目标二。确定IDH（1 R132 H）表位如何被IDH 1-TCR提呈和识别。我们将 确定与IDH 1（R132 H）表位反应的TCR的抗原特异性和亲合力。我们还将评估 IDH 1-TCR如何识别由多种HLA-II类分子呈递的表位。 目标3.在临床前模型中确定ACT与IDH 1-TCR-Th 1细胞的疗效和机制。 使用HLA-A2. DR 1转基因小鼠，我们将评估两个相互不排斥的机制假设：1） Th 1-细胞作为细胞毒性T淋巴细胞（CTL）发挥作用并直接杀死HLA-II类+IDH 1（R132 H）+神经胶质瘤细胞， 和2）Th 1-细胞促进CD 8 + CTL的交叉致敏，其继而杀死胶质瘤细胞。