title: A vaccine targeting mutant IDH1 induces antitumour immunity.
abstract: 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 (TH1) responses. CD4(+) TH1 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.
authors.affiliation: 1] Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [3].
authors.forename: Theresa
authors.initials: T
authors.lastname: Schumacher
authors.affiliation: 1] Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [3].
authors.forename: Lukas
authors.initials: L
authors.lastname: Bunse
authors.affiliation: 1] Department of Neuropathology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pusch
authors.affiliation: 1] Department of Neuropathology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Sahm
authors.affiliation: 1] Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK) Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Wiestler
authors.affiliation: Department of Translational Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Quandt
authors.affiliation: Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Menn
authors.affiliation: 1] Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK) Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Osswald
authors.affiliation: 1] Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Iris
authors.initials: I
authors.lastname: Oezen
authors.affiliation: 1] Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Ott
authors.affiliation: 1] Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Keil
authors.affiliation: 1] German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Balß
authors.affiliation: 1] Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Rauschenbach
authors.affiliation: Department of Immunotherapy and -prevention Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Agnieszka K
authors.initials: AK
authors.lastname: Grabowska
authors.affiliation: Ribological GmbH, 55131 Mainz, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Vogler
authors.affiliation: Translational Oncology, 55131 Mainz, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Diekmann
authors.affiliation: Department of Immunology, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Nico
authors.initials: N
authors.lastname: Trautwein
authors.affiliation: Department of Translational Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Stefan B
authors.initials: SB
authors.lastname: Eichmüller
authors.affiliation: Metabolic Centre Heidelberg, University Children's Hospital, 69120 Heidelberg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Okun
authors.affiliation: Department of Immunology, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Stevanović
authors.affiliation: Department of Immunotherapy and -prevention Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Angelika B
authors.initials: AB
authors.lastname: Riemer
authors.affiliation: Translational Oncology, 55131 Mainz, Germany.
authors.forename: Ugur
authors.initials: U
authors.lastname: Sahin
authors.affiliation: Center for Molecular Neurobiology, University Medical Center, Hamburg-Eppendorf, 20251 Hamburg, Germany.
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Friese
authors.affiliation: Department of Translational Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Beckhove
authors.affiliation: 1] Department of Neuropathology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.affiliation: 1] Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK) Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.affiliation: 1] Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Platten
mesh_terms: D000818:Animals; D000918:Antibody Specificity; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology* / Q000627:therapeutic use*; D005260:Female; D005910:Glioma / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D056724:Immunity, Humoral; D007167:Immunotherapy / Q000379:methods; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000276:immunology*; D008297:Male; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics / Q000276:immunology*; D009154:Mutation; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D000949:Histocompatibility Antigens Class II; D050505:Mutant Proteins; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human