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A vaccine targeting mutant IDH1 induces antitumour immunity

机译：针对突变IDH1的疫苗诱导抗肿瘤免疫

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摘要

Monoallelic point mutations of isocitrate dehydrogenase type 1 (IDH1) are an early and defining event in the development of a subgroup of gliomas and other types of tumour. They almost uniformly occur in the critical arginine residue (Arg 132) in the catalytic pocket, resulting in a neomorphic enzymatic function, production of the oncometabolite 2-hydroxyglutarate (2-HG), genomic hypermethylation, genetic instability and malignant transformation. More than 70% of diffuse grade Ⅱ and grade Ⅲ gliomas carry the most frequent mutation, IDH1(R132H) (ref. 3). From an immunological perspective, IDH1(R132H) represents a potential target for immunotherapy as it is a tumour-specific potential neoantigen with high uniformity and penetrance expressed in all tumour cells. Here we demonstrate that IDH1(R132H) contains an immunogenic epitope suitable for mutation-specific vaccination. Peptides encompassing the mutated region are presented on major histocompatibility complexes (MHC) class Ⅱ and induce mutation-specific CD4~+ T-helper-1 (T_H1) responses. CD4~+ T_H1 cells and antibodies spontaneously occurring in patients with IDH1(R132H)-mutated gliomas specifically recognize IDH1(R132H). Peptide vaccination of mice devoid of mouse MHC and transgenic for human MHC class Ⅰ and Ⅱ with IDH1(R132H) p123-142 results in an effective MHC class Ⅱ-restricted mutation-specific antitumour immune response and control of pre-established syngeneic IDH1(R132H)-expressing tumours in a CD4~+ T-cell-dependent manner. As IDH1 (R132H) is present in all tumour cells of these slow-growing gliomas, a mutation-specific anti-IDH1 (R132H) vaccine may represent a viable novel therapeutic strategy for IDH1(R132H)-mutated tumours.
机译：1型异柠檬酸脱氢酶（IDH1）的单等位基因点突变是神经胶质瘤亚组和其他类型肿瘤发展过程中的早期事件。它们几乎均匀地出现在催化口袋中的关键精氨酸残基（Arg 132）中，导致新形态的酶功能，合成代谢物2-羟基戊二酸（2-HG）的产生，基因组高甲基化，遗传不稳定和恶性转化。超过70％的弥散性Ⅱ级和Ⅲ级神经胶质瘤携带最常见的突变IDH1（R132H）（参考文献3）。从免疫学的角度来看，IDH1（R132H）代表了免疫治疗的潜在靶标，因为它是一种肿瘤特异性潜在的新抗原，在所有肿瘤细胞中均具有很高的均匀性和渗透性。在这里，我们证明IDH1（R132H）包含适合突变特异性疫苗接种的免疫原性表位。 Ⅱ类主要组织相容性复合物（MHC）上存在包含突变区域的肽，并诱导突变特异性CD4〜+ T-helper-1（T_H1）反应。 IDH1（R132H）突变神经胶质瘤患者中自发出现的CD4 + T_H1细胞和抗体特异性识别IDH1（R132H）。不含小鼠MHC且对人MH和I类MHC进行转基因的小鼠疫苗接种IDH1（R132H）p123-142可产生有效的MHCⅡ类限制性突变特异性抗肿瘤免疫反应并控制预先建立的同基因IDH1（R132H）以CD4〜+ T细胞依赖性方式表达肿瘤。由于这些缓慢生长的神经胶质瘤的所有肿瘤细胞中都存在IDH1（R132H），因此，突变特异性抗IDH1（R132H）疫苗可能代表了IDH1（R132H）突变肿瘤的可行新治疗策略。

著录项

  • 来源
    《Nature》 |2014年第7514期|324-327|共4页
  • 作者

    Theresa Schumacher; Lukas Bunse; Stefan Pusch; Felix Sahm; Benedikt Wiestler; Jasmin Quandt; Oliver Menn; Matthias Osswald; Iris Oezen; Martina Ott; Melanie Keil; Joerg Balss; Katharina Rauschenbach; Agnieszka K. Grabowska; Isabel Vogler; Jan Diekmann; Nico Trautwein; Stefan B. Eichmueller; Juergen Okun; Stefan Stevanovic; Angelika B. Riemer; Ugur Sahin; Manuel A. Friese; Philipp Beckhove; Andreas von Deimling; Wolfgang Wick; Michael Platten;

  • 作者单位

    Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany,German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;

    Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany,German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;

    Department of Neuropathology, University Hospital Heidelberg and National Center for Tumor Diseases,69120 Heidelberg, Germany,German Cancer Consortium(DKTK) Clinical Cooperation Unit Neuropathology, German Cancer Ressarch Center(DKFZ), 69120 Heidelberg,Cermany;

    Department of Neuropathology, University Hospital Heidelberg and National Center for Tumor Diseases,69120 Heidelberg, Germany,German Cancer Consortium(DKTK) Clinical Cooperation Unit Neuropathology, German Cancer Ressarch Center(DKFZ), 69120 Heidelberg,Cermany;

    Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany,German Cancer Consortium(DKTK) Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ),69120 Heidelberg, Germany;

    Department of Translational Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;

    Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany;

    Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany,German Cancer Consortium(DKTK) Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ),69120 Heidelberg, Germany;

    Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany,German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;

    Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany,German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;

    Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany,German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;

    German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany,German Cancer Consortium(DKTK) Clinical Cooperation Unit Neuropathology, German Cancer Ressarch Center(DKFZ), 69120 Heidelberg,Cermany;

    Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany,German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;

    Department of Immunotherapy and -prevention Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;

    Ribological GmbH, 55131 Mainz, Germany;

    Translational Oncology, 55131 Mainz, Germany;

    Department of Immunology, University of Tubingen, 72076 Tubingen, Germany;

    Department of Translational Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;

    Metabolic Centre Heidelberg, University Children's Hospital, 69120 Heidelberg, Germany;

    Department of Immunology, University of Tubingen, 72076 Tubingen, Germany;

    Department of Immunotherapy and -prevention Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;

    Translational Oncology, 55131 Mainz, Germany;

    Center for Molecular Neurobiology, University Medical Center, Hamburg-Eppendorf, 20251 Hamburg, Germany;

    Department of Translational Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;

    Department of Neuropathology, University Hospital Heidelberg and National Center for Tumor Diseases,69120 Heidelberg, Germany,German Cancer Consortium(DKTK) Clinical Cooperation Unit Neuropathology, German Cancer Ressarch Center(DKFZ), 69120 Heidelberg,Cermany;

    Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany,German Cancer Consortium(DKTK) Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ),69120 Heidelberg, Germany;

    Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany,German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;

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