A vaccine targeting mutant IDH1 induces antitumour immunity

The mutant IDH1 protein, which is expressed in a large fraction of human gliomas, is shown to be immunogenic; mutant-specific immune responses can be detected in patients with IDH1 mutated gliomas and generated in mice and are shown to treat established IDH1 mutant tumours in a syngeneic MHC humanized mouse model in a CD4 T-cell-dependent manner. Isocitrate dehydrogenase type 1 (IDH1) point mutations are associated with certain slow-growing gliomas and other tumours. This study in a humanized syngeneic tumour mouse model shows that IDH1(R132H), the mutant IDH1 protein most commonly expressed in gliomas, is immunogenic, capable of inducing a human MHC class II-restricted spontaneous and functionally relevant immune response. These findings suggest that some patients with gliomas with a high prevalence of the IDH1(R132H) mutation may benefit from a tumour vaccine based on the IDH1(R132H) antigen. Monoallelic point mutations of isocitrate dehydrogenase type 1 (IDH1) are an early and defining event in the development of a subgroup of gliomas1,2,3 and other types of tumour4,5,6. 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 hypermethylation9,10,11, genetic instability and malignant transformation12. 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 cells13,14. 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 gliomas15, a mutation-specific anti-IDH1(R132H) vaccine may represent a viable novel therapeutic strategy for IDH1(R132H)-mutated tumours.