A vaccine targeting mutant IDH1 induces antitumour immunity
Standard
A vaccine targeting mutant IDH1 induces antitumour immunity. / Schumacher, Theresa; Bunse, Lukas; Pusch, Stefan; Sahm, Felix; Wiestler, Benedikt; Quandt, Jasmin; Menn, Oliver; Osswald, Matthias; Oezen, Iris; Ott, Martina; Keil, Melanie; Balß, Jörg; Rauschenbach, Katharina; Grabowska, Agnieszka K; Vogler, Isabel; Diekmann, Jan; Trautwein, Nico; Eichmüller, Stefan B; Okun, Jürgen; Stevanović, Stefan; Riemer, Angelika B; Sahin, Ugur; Friese, Manuel A; Beckhove, Philipp; von Deimling, Andreas; Wick, Wolfgang; Platten, Michael.
in: NATURE, Jahrgang 512, Nr. 7514, 21.08.2014, S. 324-7.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - A vaccine targeting mutant IDH1 induces antitumour immunity
AU - Schumacher, Theresa
AU - Bunse, Lukas
AU - Pusch, Stefan
AU - Sahm, Felix
AU - Wiestler, Benedikt
AU - Quandt, Jasmin
AU - Menn, Oliver
AU - Osswald, Matthias
AU - Oezen, Iris
AU - Ott, Martina
AU - Keil, Melanie
AU - Balß, Jörg
AU - Rauschenbach, Katharina
AU - Grabowska, Agnieszka K
AU - Vogler, Isabel
AU - Diekmann, Jan
AU - Trautwein, Nico
AU - Eichmüller, Stefan B
AU - Okun, Jürgen
AU - Stevanović, Stefan
AU - Riemer, Angelika B
AU - Sahin, Ugur
AU - Friese, Manuel A
AU - Beckhove, Philipp
AU - von Deimling, Andreas
AU - Wick, Wolfgang
AU - Platten, Michael
PY - 2014/8/21
Y1 - 2014/8/21
N2 - 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.
AB - 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.
KW - Animals
KW - Antibody Specificity
KW - Antigens, Neoplasm
KW - Cancer Vaccines
KW - Female
KW - Glioma
KW - Histocompatibility Antigens Class II
KW - Humans
KW - Immunity, Humoral
KW - Immunotherapy
KW - Isocitrate Dehydrogenase
KW - Male
KW - Mice
KW - Mutant Proteins
KW - Mutation
KW - T-Lymphocytes, Helper-Inducer
KW - Xenograft Model Antitumor Assays
U2 - 10.1038/nature13387
DO - 10.1038/nature13387
M3 - SCORING: Journal article
C2 - 25043048
VL - 512
SP - 324
EP - 327
JO - NATURE
JF - NATURE
SN - 0028-0836
IS - 7514
ER -