A vaccine targeting mutant IDH1 in newly diagnosed glioma

Nature. 2021 Apr;592(7854):463-468. doi: 10.1038/s41586-021-03363-z. Epub 2021 Mar 24.


Mutated isocitrate dehydrogenase 1 (IDH1) defines a molecularly distinct subtype of diffuse glioma1-3. The most common IDH1 mutation in gliomas affects codon 132 and encodes IDH1(R132H), which harbours a shared clonal neoepitope that is presented on major histocompatibility complex (MHC) class II4,5. An IDH1(R132H)-specific peptide vaccine (IDH1-vac) induces specific therapeutic T helper cell responses that are effective against IDH1(R132H)+ tumours in syngeneic MHC-humanized mice4,6-8. Here we describe a multicentre, single-arm, open-label, first-in-humans phase I trial that we carried out in 33 patients with newly diagnosed World Health Organization grade 3 and 4 IDH1(R132H)+ astrocytomas (Neurooncology Working Group of the German Cancer Society trial 16 (NOA16), ClinicalTrials.gov identifier NCT02454634). The trial met its primary safety endpoint, with vaccine-related adverse events restricted to grade 1. Vaccine-induced immune responses were observed in 93.3% of patients across multiple MHC alleles. Three-year progression-free and death-free rates were 0.63 and 0.84, respectively. Patients with immune responses showed a two-year progression-free rate of 0.82. Two patients without an immune response showed tumour progression within two years of first diagnosis. A mutation-specificity score that incorporates the duration and level of vaccine-induced IDH1(R132H)-specific T cell responses was associated with intratumoral presentation of the IDH1(R132H) neoantigen in pre-treatment tumour tissue. There was a high frequency of pseudoprogression, which indicates intratumoral inflammatory reactions. Pseudoprogression was associated with increased vaccine-induced peripheral T cell responses. Combined single-cell RNA and T cell receptor sequencing showed that tumour-infiltrating CD40LG+ and CXCL13+ T helper cell clusters in a patient with pseudoprogression were dominated by a single IDH1(R132H)-reactive T cell receptor.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cancer Vaccines / immunology*
  • Cancer Vaccines / therapeutic use*
  • Cells, Cultured
  • Disease Progression
  • Female
  • Glioma / diagnosis*
  • Glioma / genetics
  • Glioma / immunology
  • Glioma / therapy*
  • Humans
  • Isocitrate Dehydrogenase / genetics*
  • Isocitrate Dehydrogenase / immunology*
  • Male
  • Mutant Proteins / genetics
  • Mutant Proteins / immunology
  • Mutation*
  • Phenotype
  • Receptors, Antigen, T-Cell / immunology
  • Survival Rate
  • T-Lymphocytes / immunology


  • Cancer Vaccines
  • Mutant Proteins
  • Receptors, Antigen, T-Cell
  • Isocitrate Dehydrogenase
  • IDH1 protein, human

Associated data

  • ClinicalTrials.gov/NCT02454634