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A vaccine targeting mutant IDH1 induces antitumour immunity.

Nature (2014-07-22)
Theresa Schumacher, Lukas Bunse, Stefan Pusch, Felix Sahm, Benedikt Wiestler, Jasmin Quandt, Oliver Menn, Matthias Osswald, Iris Oezen, Martina Ott, Melanie Keil, Jörg Balß, Katharina Rauschenbach, Agnieszka K Grabowska, Isabel Vogler, Jan Diekmann, Nico Trautwein, Stefan B Eichmüller, Jürgen Okun, Stefan Stevanović, Angelika B Riemer, Ugur Sahin, Manuel A Friese, Philipp Beckhove, Andreas von Deimling, Wolfgang Wick, Michael Platten
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Isocitric Dehydrogenase (NADP) from porcine heart, Type IV, buffered aqueous glycerol solution, 3-20 units/mg protein
Sigma-Aldrich
Isocitric Dehydrogenase (NADP) from porcine heart, Type I, 0.5-3.0 unit/mg solid (plus numerous enzyme activities associated with porcine heart)
Sigma-Aldrich
Isocitrate Dehydrogenase 1 (NADP+) human, recombinant, expressed in Sf9 cells, ≥90% (SDS-PAGE)
Sigma-Aldrich
Isocitrate Dehydrogenase 1 (NADP+) human, recombinant, expressed in E. coli, lyophilized powder, ≥80 units/mg protein