A vaccine targeting mutant IDH1 induces antitumour immunity

T Schumacher, L Bunse, S Pusch, F Sahm, B Wiestler… - Nature, 2014 - nature.com
T Schumacher, L Bunse, S Pusch, F Sahm, B Wiestler, J Quandt, O Menn, M Osswald…
Nature, 2014nature.com
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 …
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. ). 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.
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