A vaccine targeting mutant IDH1 induces antitumour immunity.

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.

• Authors: 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
• Journal: Nature (Nature) Vol. 512 Issue 7514 Pg. 324-7 (Aug 21 2014) ISSN: 1476-4687 [Electronic] England
• PMID: 25043048 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Cancer Vaccines
• Histocompatibility Antigens Class II
• Mutant Proteins
• Isocitrate Dehydrogenase
• IDH1 protein, human

Topics

• Animals
• Antibody Specificity
• Antigens, Neoplasm (genetics, immunology)
• Cancer Vaccines (immunology, therapeutic use)
• Female
• Glioma (enzymology, genetics, immunology, therapy)
• Histocompatibility Antigens Class II (immunology)
• Humans
• Immunity, Humoral
• Immunotherapy (methods)
• Isocitrate Dehydrogenase (genetics, immunology)
• Male
• Mice
• Mutant Proteins (genetics, immunology)
• Mutation
• T-Lymphocytes, Helper-Inducer (immunology)
• Xenograft Model Antitumor Assays