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A vaccine targeting mutant IDH1 induces antitumour immunity

Nature volume 512, pages 324–327 (2014)Cite this article

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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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Figure 1: IDH1(R132H) peptide vaccination induces TH1 and humoral responses in A2.DR1 mice.
Figure 2: Spontaneous TH1 and humoral IDH1(R132H)-specific responses are detected in IDH1(R132H)+ glioma patients.
Figure 3: IDH1(R132H) peptide vaccination reduces IDH1(R132H)+ tumour growth in A2.DR1 mice.
Figure 4: Growth suppression of pre-established IDH1(R132H)+ tumours by IDH1(R132H) peptide vaccination is dependent on TH cells.

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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

  1. Theresa Schumacher and Lukas Bunse: These authors contributed equally to this work.

Authors and 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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  1. Theresa Schumacher
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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.

Corresponding author

Correspondence to Michael Platten.

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The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 IDH1 peptide libraries are used to assess MHC binding and immunogenicity in silico, in vitro and in vivo.

a, Human wild-type IDH1 (WT) and IDH1(R132H) (RH) amino acid sequences covering the mutated residue. b, c, Peptide libraries of wild-type IDH1 and IDH1(R132H) containing peptides of 10 (b) or 15 (c) amino acids were generated. d, e, MHC peptide binding predictions for IDH1(R132H) peptides to HLA-A*0201 (A2) using NetMHC algorithm (d) and SYFPEITHI (e). f, IDH1(R132H) 10-mer peptide binding to HLA-A2 in vitro in a T2 binding assay. Fluorescence intensities are depicted after background subtraction. g, DR1-binding wild-type IDH1 15-mer epitopes were identified by Reveal Class II binding assay using the 15-mer peptide library (c). Immediate binding (yellow) and 24-h stability (red). h–j, ELISpots of IFN-γ splenocyte responses to 10-mers (h, j) and 15-mers (i) after vaccination of A2.DR1 mice with IDH1(R132H) in Montanide (j) or vehicle in CFA (h, i) (red, IDH1(R132H) (p123–142); blue, WT IDH1 (p123–142); black, IDH1(R132H) library; p123–142 (R132H versus WT), Welch t-test; library, ANOVA; n = 3 biological replicates). Error bars, mean + s.e.m.

Extended Data Figure 2 T-helper cell characterization after IDH1(R132H) peptide vaccination in HLA-DR transgenic mice.

a, Cytokine ELISAs of splenocyte responses to IDH1(R132H) (p123–142) or vehicle after vaccination of three A2.DR1 (top and middle panels) and three DR4 (bottom panel) mice with IDH1(R132H) (red) or vehicle (black) in CFA (top panel) or Montanide (middle and bottom panels; Welch t-test; n = 3 technical replicates). Error bars, mean + s.e.m. b, Representative intracellular flow cytometry of splenocyte responses to IDH1(R132H) (p123–142) or vehicle after vaccination of three A2.DR1 (left and middle panels) and three DR4 (right panel) mice with IDH1(R132H) (vacc) or vehicle (sham) using CFA (left panel) or Montanide (middle and right panels). Gated on CD4+ cells; red numbers indicate populations in per cent. c, ELISpots of IFN-γ splenocyte responses to IDH1 (p123–142) (R132H, wild type) after vaccination of DR4 mice with IDH1(R132H) (vacc) or vehicle (sham) in Montanide (Welch t-test; n = 3 biological replicates). Error bars, mean + s.e.m.

Extended Data Figure 3 IDH1(R132H)-specific CD4+ T cells have a TH1 phenotype and are dependent on HLA-DRA*0101 HLA-DRB1*0101 (DR1).

a, Intracellular flow cytometry of IDH1(R132H)-specific T-cell line response to IDH1(R132H) (p123–142) or vehicle. Gated on CD4+ cells; red numbers indicate populations in per cent. b, c, ELISpots of an IDH1(R132H)-specific T-cell clone (white, MOG; black, vehicle; red, IDH1(R132H); blue, wild-type IDH1; b, Welch t-test, error bars, mean ± s.e.m.; c, pairwise Welch t-test with Bonferroni correction; error bars, mean + s.e.m. n = 3 technical replicates).

Extended Data Figure 4 IDH1 peptide-coated ELISA for detection of IDH1-specific IgG in human and mouse serum.

a, Sandwich ELISA scheme. b, ELISA was established using mouse anti-IDH1(R132H) antibody as serum substitute. ELISA on indicated peptides of the 10-mer and 15-mer libraries (blue, wild-type IDH1; red, IDH1(R132H); 10-mer pool, all library peptides) and a negative control peptide (white, HIV) (left). p122–136 (R132H) was used to titrate the anti-IDH1(R132H) antibody (middle). IgG subtype-specific secondary antibodies were used with IDH1(R132H)-specific antibody on IDH1 p122–136 (red, IDH1(R132H); blue, wild-type IDH1) (right). c, Detection of IDH1(R132H)-specific IgG in IDH1(R132H)+ patient serum. IDH1 peptides of the 15-mer library and p123–142 (blue, wild type; red, R132H) were used to establish the ELISA for patient serum with MOG as negative control peptide. Serum from patients p009 and p078 was used. Scatter plot showing individual values and the mean. d, Detection of tetanus toxoid-specific IgG in serum from patients with wild-type IDH1 gliomas (blue, n = 44) and IDH1(R132H)+ gliomas (red, n = 40). IDH1(R132H)+ are grouped into IDH1(R132H)-IgG positive (responder, n = 4) and negative (non-responder, n = 36) according to Fig. 2g (Wilcoxon rank-sum test). Scatter plot showing individual values and the mean. e, IDH1(R132H)-specific IgG and IgG subtypes IgG1, IgG2, IgG3 and IgG4 were detected by p122–136 (R132H)-coated ELISA in serum from IDH1(R132H)+ glioma patients with increased relative values for IDH1(R132H)-specific IgG (pairwise Welch t-test with Bonferroni correction; n = 10). Scatter plot showing individual values for each patient and the mean.

Extended Data Figure 5 Generation and characterization of syngeneic IDH1(R132H)+ A2.DR1 sarcoma cells.

a, Scheme for establishment of syngeneic A2.DR1 sarcoma cell line. b, Haematoxylin and eosin staining of established A2.DR1 sarcoma cell line. c, IDH1(R132H) expression in transduced A2.DR1 sarcoma cells by immunofluorescent staining (top) and by western blot (bottom). d, 2-HG concentrations (upper panel) and IDH1(R132H) expression by western blot (lower panel) in transduced A2.DR1 syngeneic sarcoma cells in vitro (left), A2.DR1 sarcomas in vivo (IVC1) and human gliobastoma (RH) and anaplastic astrocytoma (wt) tissue (right). Red dashed lines mark the range of 2-HG concentrations found in glioma tissue. e, Growth of subcutaneous sarcomas (IDH1(R32H)+, red; wild-type IDH1+, blue) (Wilcoxon rank-sum test for median AUC; n = 5). Error bars, mean ± s.e.m. f, g, ELISA (f) and ELISpot (g, after subtraction of MOG-induced spots) of IFN-γ splenocyte responses to IDH1(R132H) (p123–142) after preventive vaccination with IDH1(R132H) (red) or vehicle (black) and injection with IDH1(R132H)+ or wild-type IDH1+ sarcomas (Welch t-test; n = 8 IDH1(R123H) tumours, vaccinated mice; n = 6 IDH1(R132H) tumours, sham mice; and wild-type IDH1 tumours, vaccinated mice; n = 5 wild-type IDH1 tumours, sham mice). Error bars, mean + s.e.m. h–j, IDH1/2 enzymatic activity in liver and brain (h), and ELISpot (i, after subtraction of MOG-induced spots, negative values set to zero) and ELISA (j) of IFN-γ splenocyte (spleen) and lymph node (LN) responses to IDH1 (p123-142) (RH, wild type) after therapeutic vaccination with IDH1(R132H) (red) or vehicle (black) and injection with IDH1(R132H)+ sarcomas (Welch t-test; n = 6, vaccinated; n = 5, sham (h); n = 7, vaccinated; n = 6, sham (i, j). Scatter plots showing individual values and the mean. All n values indicate number of biological replicates.

Extended Data Figure 6 NY-ESO-1 is a suitable antigen for DR1-dependent and TH-mediated therapeutic peptide vaccination in A2.DR1 mice.

a, Alignment of human NY-ESO-1 protein with murine CTAG2 protein. Red box, HLA-DRA*0101 DRB1*0101 (DR1)-restricted epitope human NY-ESO-1 p119–143. b, NY-ESO-1 protein detection by immunofluorescent staining and western blot in A2.DR1 sarcoma cells. c, d, ELISpot (c, after subtraction of MOG-induced spots, Wilcoxon rank-sum test, n = 7 biological replicates, error bars, mean + s.e.m.) and representative intracellular flow cytometry (d, gated on CD4+ T cells, red numbers, populations in per cent) of IFN- γ splenocyte (spleen) and lymph node (c, LN) responses to NY-ESO-1 after therapeutic vaccination with NY-ESO-1 (red) or vehicle (black) and injection with NY-ESO-1+ sarcomas.

Extended Data Figure 7 IDH1(R132H) peptide vaccination induces TH responses in A2.DR1 mice.

a, ELISpot of IFN-γ responses to IDH1 (p123–142) of CD4+ and CD8+ T cells after vaccination with IDH1(R132H) in Montanide or established T cell line (R132H, red; wild type, blue) or MOG (white), or with PMA and ionomycin (black) (Welch t-test; n = 3 technical replicates). Error bars, mean + s.e.m. b, c, Representative flow cytometry of blood lymphocytes from A2.DR1 mice depleted of CD4+ T cells by clone GK1.5 (b) and of B cells by clone 1D3, or isotype control treated with clone LTF-2 (b) or clone 2A3 (c), and immunized with IDH1(R132H) (vacc) or vehicle (sham). Red numbers indicate populations in per cent. d, ELISpot of IFN-γ splenocyte (spleen) and lymph node (LN) responses to IDH1 p123–142 (RH and wild type) after therapeutic vaccination with IDH1(R132H) and depletion of B cells (blue) or isotype-control treatment (red) or with vehicle (black) (Welch one-way ANOVA and pairwise Welch t-tests with Bonferroni correction; n = 6 biological replicates). Scatter plots showing individual values after subtraction of MOG-induced spots and the mean. e, Growth of IDH1(R132H)+ subcutaneous sarcomas after therapeutic vaccination with IDH1(R132H) and depletion of B cells (blue) or isotype-control treatment (red) or with vehicle (black) (Wilcoxon rank-sum test for median AUC with Bonferroni correction; n = 6 per group, n = 7 for vaccinated without depletion). Error bars, mean ± s.e.m.

Extended Data Table 1 Patient characteristics and analyses
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Extended Data Table 2 Clinical information of patients with IDH1 mutated gliomas
Full size table
Extended Data Table 3 Pathological analysis of organs from preventively vaccinated A2.DR1
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Schumacher, T., Bunse, L., Pusch, S. et al. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature 512, 324–327 (2014). https://doi.org/10.1038/nature13387

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