Journal
NATURE
Volume 512, Issue 7514, Pages 324-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature13387
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Funding
- DKFZ Light Microscopy and Genomics and Proteomics Facilities
- NIH
- Interdisciplinary Research Program of the National Center for Tumor Diseases Heidelberg [IFP III/2]
- Wilhelm Sander Foundation [2012.118.1]
- Helmholtz Foundation [VH-NG-306]
- Andreas Zimprich Foundation
- German Research Foundation [SFB938]
- Helmholtz International Graduate School
- Heinrich F. C. Behr Foundation
- Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology MD/PhD program, University Heidelberg
- University Hospital Heidelberg
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Monoallelic point mutations of isocitrate dehydrogenase type 1 (IDH1) are an early and defining event in the development of a subgroup of gliomas(1-3) and other types of tumour(4-6). 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)(7,8), genomic hypermethylation9-11, genetic instability and malignant transformation(12). 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(13,14). Here we demonstrate that IDH1(R132H) contains an immunogenic epitope suitable formutation-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. CD41 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-restrictedmutation-specific antitumourimmune 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(15), a mutation-specific anti-IDH1(R132H) vaccine may represent a viable novel therapeutic strategy for IDH1(R132H)-mutated tumours.
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