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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.

摘要