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.

抽象的 异位酸脱氢酶（IDH）酶IDH1和IDH2的突变是早期的，并且经常遗传 WHO II级或III级下级弥漫性神经胶质瘤（LGG）以及继发性胶质母细胞瘤的改变， 从LGG进展。尽管IDH突变体（IDH-MUT）LGG与更长的生存有关 与IDH野生型（IDH-WT）LGG相比，大多数IDH-MUT LGG患者最终屈服于该疾病。 IDH-MUT患者的诊断中位年龄比IDH-WT患者年轻，这表明更多 IDH-MUT患者的治疗机会，例如免疫疗法。所有IDH1和IDH2突变会议 通过将α-酮戊二酸（αkg）转化为2-羟基戊二酸（R-）（r-）的（r）源性体（R- 2HG）和协调全基因组的表观遗传学变化。所有IDH突变中约有90％是一个 IDH1的位置132的碱基突变用组氨酸（H; R132H）代替精氨酸（R）。作为针对的方式 IDH1（R132H）通过免疫疗法衍生的发作，我们最近克隆了T细胞受体（TCR）的cDNA， 特别针对IDH1（R132H）衍生的肽发作（IDH1-TCR）反应。没有免疫疗法， 已知LGG被相对较少的T细胞渗透，这意味着LGG可能表现出独特的 免疫抑制机制。为了支持这一点，我们最近证明了IDH突变和R- 2HG导致效应子T细胞吸收趋化因子（例如CXCL10），从而抑制浸润 神经胶质瘤中效应T细胞。我们的数据还表明，突变体IDH1特异性抑制剂已恢复了CXCL10和 提高了基于T细胞的免疫疗法在IDH-MUT神经胶质瘤的临床前小鼠模型中的效率。 最后，我们的数据表明R-2HG还抑制了髓样细胞的CXCL10产生。在电流中 提案，我们将基于这些数据来评估我们的中心假设，即IDH-MUT GLIOMA可能是 通过适当调节LGG微环境和靶向，易受免疫疗法 IDH1（R132H）衍生的Neoantigen情节。我们将测试以下特定目标： AIM 1。确定IDH突变对神经胶质瘤浸润的髓样细胞的影响。因为髓样细胞可以 充当抗原呈递细胞（APC），我们将描述IDH突变对神经胶质瘤浸润的影响 髓样细胞并确定抑制突变体IDH是否可以促进其APC功能。 AIM 2。确定如何通过IDH1-TCR提出和认可IDH（1R132H）发作。我们将 确定TCR对IDH1（R132H）表位反应的TCR的抗原特异性和亲和力。我们还将评估 IDH1-TCR如何识别由多种HLA级II分子提出的发作。 AIM 3。在临床前模型中使用IDH1-TCR-TH1细胞确定ACT的效率和机制。 使用HLA-A2.DR1转基因小鼠，我们将评估两个相互非排他性的机械假设：1） Th1细胞充当细胞毒性T淋巴细胞（CTL），直接杀死HLA级II+ IDH1（R132H）+神经胶质瘤细胞， 2）Th1细胞促进CD8+ CTL的交叉染色，进而杀死神经胶质瘤细胞。