权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
10436184
负责人：
Hideho Okada
金额：
$ 36.2万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
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/10436184
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 insight mouse model mutant neoantigens novel phase 1 study pre-clinical trafficking vaccine efficacy

项目摘要

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.

抽象的异柠檬酸脱氢酶 (IDH) IDH1 和 IDH2 的突变是早期且频繁的遗传突变 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， LGG 的进展。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 患者的诊断中位年龄比 IDH-WT 患者更年轻，这表明 IDH-MUT 患者的诊断中位年龄比 IDH-WT 患者更年轻。 IDH-MUT 患者的治疗机会，例如免疫疗法。所有 IDH1 和 IDH2 突变都赋予通过将 α-酮戊二酸 (αKG) 转化为 2-羟基戊二酸 (R-) 的 (R)-对映体，获得新的功能活性 2HG），并协调全基因组表观遗传变化。大约 90% 的 IDH 突变是单一突变 IDH1 132 位碱基突变，用组氨酸（H；R132H）取代精氨酸（R）。作为一种瞄准目标的方法通过免疫疗法获得 IDH1 (R132H) 衍生表位，我们最近克隆了 T 细胞受体 (TCR) 的 cDNA，与 IDH1(R132H) 衍生肽表位 (IDH1-TCR) 发生特异性反应。如果没有免疫治疗，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 T 细胞吸引趋化因子（例如 CXCL10）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 IDH1 特异性抑制剂恢复了 CXCL10 和增强了基于 T 细胞的免疫疗法在 IDH-MUT 神经胶质瘤临床前小鼠模型中的疗效。最后，我们的数据表明 R-2HG 还抑制骨髓细胞产生 CXCL10。在当前提案中，我们将根据这些数据来评估我们的中心假设，即 IDH-MUT 神经胶质瘤可能是通过适当调节 LGG 微环境和靶向 IDH1(R132H)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性骨髓细胞的影响。正如骨髓细胞可以作为抗原呈递细胞 (APC)，我们将描述 IDH 突变对神经胶质瘤浸润的影响骨髓细胞并确定抑制突变 IDH 是否可以促进其 APC 功能。目标 2. 确定 IDH(1R132H) 表位如何呈递并被 IDH1-TCR 识别。我们将确定与 IDH1(R132H) 表位反应的 TCR 的抗原特异性和亲合力。我们也会评估 IDH1-TCR 如何识别各种 HLA-II 类分子呈现的表位。目标 3. 在临床前模型中确定 IDH1-TCR-Th1 细胞 ACT 的功效和机制。使用 HLA-A2.DR1 转基因小鼠，我们将评估两个相互非排斥的机制假设：1) Th1 细胞作为细胞毒性 T 淋巴细胞 (CTL) 发挥作用，直接杀死 HLA-II 类 + IDH1(R132H)+ 神经胶质瘤细胞， 2) Th1 细胞促进 CD8+ CTL 的交叉启动，进而杀死神经胶质瘤细胞。