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.
%0 Journal Article
%1 Schumacher:2014:Nature:25043048
%A Schumacher, T
%A Bunse, L
%A Pusch, S
%A Sahm, F
%A Wiestler, B
%A Quandt, J
%A Menn, O
%A Osswald, M
%A Oezen, I
%A Ott, M
%A Keil, M
%A Balß, J
%A Rauschenbach, K
%A Grabowska, A K
%A Vogler, I
%A Diekmann, J
%A Trautwein, N
%A Eichmüller, S B
%A Okun, J
%A Stevanović, S
%A Riemer, A B
%A Sahin, U
%A Friese, M A
%A Beckhove, P
%A von Deimling, A
%A Wick, W
%A Platten, M
%D 2014
%J Nature
%K IDH1 SHOULDREAD cancer-research glioma immunotherapy
%N 7514
%P 324-327
%R 10.1038/nature13387
%T A vaccine targeting mutant IDH1 induces antitumour immunity
%U https://www.ncbi.nlm.nih.gov/pubmed/25043048
%V 512
%X 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.
@article{Schumacher:2014:Nature:25043048,
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. },
added-at = {2018-12-19T13:47:45.000+0100},
author = {Schumacher, T and Bunse, L and Pusch, S and Sahm, F and Wiestler, B and Quandt, J and Menn, O and Osswald, M and Oezen, I and Ott, M and Keil, M and Balß, J and Rauschenbach, K and Grabowska, A K and Vogler, I and Diekmann, J and Trautwein, N and Eichm{\"u}ller, S B and Okun, J and Stevanović, S and Riemer, A B and Sahin, U and Friese, M A and Beckhove, P and von Deimling, A and Wick, W and Platten, M},
biburl = {https://www.bibsonomy.org/bibtex/2eeeaabffe3dea69d25375414f423ed4b/marcsaric},
description = {A vaccine targeting mutant IDH1 induces antitumour immunity. - PubMed - NCBI},
doi = {10.1038/nature13387},
interhash = {dca2bbc3c1da31f61253e4f2f01bf75a},
intrahash = {eeeaabffe3dea69d25375414f423ed4b},
journal = {Nature},
keywords = {IDH1 SHOULDREAD cancer-research glioma immunotherapy},
month = aug,
number = 7514,
pages = {324-327},
pmid = {25043048},
timestamp = {2018-12-19T13:47:45.000+0100},
title = {A vaccine targeting mutant IDH1 induces antitumour immunity},
url = {https://www.ncbi.nlm.nih.gov/pubmed/25043048},
volume = 512,
year = 2014
}