A vaccine targeting mutant IDH1 induces antitumour immunity

作者：Schumacher, Theresa; Bunse, Lukas; Pusch, Stefan; Sahm, Felix; Wiestler, Benedikt; Quandt, Jasmin; Menn, Oliver; Osswald, Matthias; Oezen, Iris; Ott, Martina; Keil, Melanie; Balss, Joerg; Rauschenbach, Katharina; Grabowska, Agnieszka K.; Vogler, Isabel; Diekmann, Jan; Trautwein, Nico; Eichmueller, Stefan B.; Okun, Juergen; Stevanovic, Stefan; Riemer, Angelika B.; Sahin, Ugur; Friese, Manuel A.; Beckhove, Philipp; von Deimling, Andreas; Wick, Wolfgang; Platten, Michael

来源：Nature, 2014, 512(7514): 324-+.

DOI：10.1038/nature13387

• BRAIN-TUMORS
• MUTATIONS
• CELLS
• DIFFERENTIATION
• PHENOTYPE
• MELANOMA
• GLIOMAS
• MICE

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.

• 出版日期2014-8-21