A vaccine targeting mutant IDH1 induces antitumour immunity

  • 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.

Bibliographical data

Original languageEnglish
ISSN0028-0836
DOIs
Publication statusPublished - 21.08.2014
PubMed 25043048