Abstract

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.

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Acknowledgements

We are indebted to the patients and their relatives who agreed to participate in this study. We thank A. Gardyan, T. Lanz and W. Osen for technical advice, T. Lanz and A. Hertenstein for providing patient blood samples, S. Hundt for cloning, A. Habel and D. Krunic for technical support, W. Nicklas for pathological analysis, and J. Jung for graphics design. We acknowledge the support by the DKFZ Light Microscopy and Genomics and Proteomics Facilities. HLA-DRB1*01:01 MHC class II tetramer bound to IDH1(R132H) p123-142 was provided by NIH tetramer core facility. A2.DR1 mice were provided by Institut Pasteur. This work was supported by the Interdisciplinary Research Program of the National Center for Tumor Diseases Heidelberg (IFP III/2) to M.P. and A.V.D., the Wilhelm Sander Foundation (2012.118.1) to M.P and A.V.D., the Helmholtz Foundation (VH-NG-306) and the Andreas Zimprich Foundation to M.P. and the German Research Foundation (SFB938 TPK) to M.P. and W.W. T.S. and M.K. were supported by the Helmholtz International Graduate School, and L.B. was supported by the Heinrich F. C. Behr Foundation and the Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology MD/PhD program, University Heidelberg. F.S. was supported by a postdoctoral fellowship of the University Hospital Heidelberg.

Author information

Author notes

    • Theresa Schumacher
    •  & Lukas Bunse

    These authors contributed equally to this work.

Affiliations

  1. Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany

    • Theresa Schumacher
    • , Lukas Bunse
    • , Benedikt Wiestler
    • , Oliver Menn
    • , Matthias Osswald
    • , Iris Oezen
    • , Martina Ott
    • , Melanie Keil
    • , Katharina Rauschenbach
    • , Wolfgang Wick
    •  & Michael Platten
  2. German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

    • Theresa Schumacher
    • , Lukas Bunse
    • , Iris Oezen
    • , Martina Ott
    • , Melanie Keil
    • , Jörg Balß
    • , Katharina Rauschenbach
    •  & Michael Platten
  3. Department of Neuropathology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany

    • Stefan Pusch
    • , Felix Sahm
    •  & Andreas von Deimling
  4. German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

    • Stefan Pusch
    • , Felix Sahm
    • , Jörg Balß
    •  & Andreas von Deimling
  5. German Cancer Consortium (DKTK) Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

    • Benedikt Wiestler
    • , Matthias Osswald
    •  & Wolfgang Wick
  6. Department of Translational Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

    • Jasmin Quandt
    • , Stefan B. Eichmüller
    •  & Philipp Beckhove
  7. Department of Immunotherapy and –prevention Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

    • Agnieszka K. Grabowska
    •  & Angelika B. Riemer
  8. Ribological GmbH, 55131 Mainz, Germany

    • Isabel Vogler
  9. Translational Oncology, 55131 Mainz, Germany

    • Jan Diekmann
    •  & Ugur Sahin
  10. Department of Immunology, University of Tübingen, 72076 Tübingen, Germany

    • Nico Trautwein
    •  & Stefan Stevanović
  11. Metabolic Centre Heidelberg, University Children’s Hospital, 69120 Heidelberg, Germany

    • Jürgen Okun
  12. Center for Molecular Neurobiology, University Medical Center, Hamburg-Eppendorf, 20251 Hamburg, Germany

    • Manuel A. Friese

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Contributions

T.S. and L.B. designed and performed experiments, analysed data and wrote the paper. F.S. and A.v.D. provided glioma tissue and determined IDH1 status. S.P. cloned IDH1 constructs. J.B. and J.O. performed 2-HG measurements. J.Q. and P.B. generated the A2.DR1 sarcoma cell line. K.R. and M.Ot. established stable overexpressions. B.W. performed statistical analysis. I.O. and M.K. performed animal experiments. O.M. and M.Os. provided patient blood samples. A.K.G. and A.B.R. performed epitope prediction and T2 binding assays. J.D., N.T., I.V., S.S. and U.S. analysed patient samples. S.B.E. provided DR4 mice. M.A.F. and W.W. were involved in study design and data interpretation. M.P. conceptualized the study, designed experiments, interpreted data and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Michael Platten.

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DOI

https://doi.org/10.1038/nature13387

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