Nature | Vol 592 | 15 April 2021 | 463 ArticleA vaccine targeting mutant IDH1 in newly diagnosed glioma Michael Platten1,2,3 ✉, Lukas Bunse1,2, Antje Wick4,5, Theresa Bunse1,2, Lucian Le Cornet6, Inga Harting7, Felix Sahm8,9, Khwab Sanghvi1, Chin Leng Tan1, Isabel Poschke1,3, Edward Green1, Sune Justesen10, Geoffrey A. Behrens11, Michael O. Breckwoldt7, Angelika Freitag6, Lisa-Marie Rother6, Anita Schmitt12, Oliver Schnell13, Jörg Hense14, Martin Misch15, Dietmar Krex16, Stefan Stevanovic17, Ghazaleh Tabatabai18, Joachim P. Steinbach19, Martin Bendszus7, Andreas von Deimling8,9, Michael Schmitt12 & Wolfgang Wick4,5,20 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. We screened 44 patients in 7 out of 8 centres that are part of the German Cancer Consortium (DKTK) and/or the Neurooncology Working Group of the German Cancer Society (NOA; Supplementary Table 1). Of these, 33 patients were included in the trial (Extended Data Fig. 1). The reasons for exclusion are listed in Supplementary Table 2. One patient (ID16) was not vaccinated because of an adverse event (fever of unknown origin) before vaccination. Hence, 32 patients were treated and there - fore included in the safety dataset (SDS; Fig. 1). Twenty patients in the SDS (62.5%) were male and 12 (37.5%) female, and the mean age was 40.4 ± 8.95 years (mean ± s.d.). The trial population was divided into three treatment groups (TG1–TG3) on the basis of standard of care (SOC) treatment that patients had received before enrollment: radiotherapy alone (RT, TG1), three cycles of chemotherapy with TMZ alone (mono-TMZ, TG2) or combined radiochemotherapy with TMZ (RT + cTMZ, TG3) (Extended Data Fig. 1). Most patients had both radiochemotherapy and TMZ before IDH1 vaccination (n = 23, 71.9%); three (9.4%) were treated with TMZ alone and six (18.8%) underwent radiotherapy alone. The average total dose of radiotherapy (n = 29) was 59.4 Gy. Out of the 32 patients, 21 (65.6%) had World Health Organization (WHO) grade 3 astrocytoma and 11 (34.4%) had grade 4. The predomi-nant location of the astrocytomas was within the frontal lobes (23/32, 71.9%). In terms of surgery, 17 of the 32 patients (53.1%) had undergone complete resection of the tumour, 12 (37.5%) had undergone subtotal resection, and 3 (9.4%) had undergone a biopsy only. For all astrocytoma tissues with sufficient material (24 of 32; 75.0%), the methylation sub - class was defined retrospectively. Low-grade methylation accounted for 14 of these 24 astrocytomas (58.3%), and the remaining 10 (41.7%) were methylation class high grade (Fig. 1 , Supplementary Table 3).