Publication Date:
2014-07-22
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schumacher, Theresa -- Bunse, Lukas -- Pusch, Stefan -- Sahm, Felix -- Wiestler, Benedikt -- Quandt, Jasmin -- Menn, Oliver -- Osswald, Matthias -- Oezen, Iris -- Ott, Martina -- Keil, Melanie -- Balss, Jorg -- Rauschenbach, Katharina -- Grabowska, Agnieszka K -- Vogler, Isabel -- Diekmann, Jan -- Trautwein, Nico -- Eichmuller, Stefan B -- Okun, Jurgen -- Stevanovic, Stefan -- Riemer, Angelika B -- Sahin, Ugur -- Friese, Manuel A -- Beckhove, Philipp -- von Deimling, Andreas -- Wick, Wolfgang -- Platten, Michael -- England -- Nature. 2014 Aug 21;512(7514):324-7. doi: 10.1038/nature13387. Epub 2014 Jun 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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]. ; 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. ; 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. ; 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. ; 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. ; 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. ; 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. ; Metabolic Centre Heidelberg, University Children's Hospital, 69120 Heidelberg, Germany. ; Center for Molecular Neurobiology, University Medical Center, Hamburg-Eppendorf, 20251 Hamburg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043048" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antibody Specificity
;
Antigens, Neoplasm/genetics/immunology
;
Cancer Vaccines/*immunology/*therapeutic use
;
Female
;
Glioma/enzymology/genetics/*immunology/*therapy
;
Histocompatibility Antigens Class II/immunology
;
Humans
;
Immunity, Humoral
;
Immunotherapy/methods
;
Isocitrate Dehydrogenase/*genetics/*immunology
;
Male
;
Mice
;
Mutant Proteins/genetics/*immunology
;
Mutation
;
T-Lymphocytes, Helper-Inducer/immunology
;
Xenograft Model Antitumor Assays
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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