Abstract
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.
Highlights
Two patients (ID19, ID21) were enrolled but could not be evaluated for immunogenicity testing and were excluded from the immunogenicity analysis
On the basis of preclinical data[4,5,8] and the observations that neither actively cytotoxic cytokine-producing ex vivo CD8+ lesion-infiltrating leukocytes (LILs) nor selected CD8+ T cell clonotype-retrieved T cell receptor (TCR)-transgenic cells reacted to IDH1(R132H) (Extended Data Fig. 11), we focused on CD4+ T cells
NOA16 met its primary endpoints by demonstrating the safety and immunogenicity of IDH1-vac in patients with newly diagnosed WHO grade 3 and 4 IDH1(R132H)+ astrocytomas without further positive prognostic factors
Summary
Michael Platten1,2,3 ✉, Lukas Bunse[1,2], Antje Wick[4,5], Theresa Bunse[1,2], Lucian Le Cornet[6], Inga Harting[7], Felix Sahm[8,9], Khwab Sanghvi[1], Chin Leng Tan[1], Isabel Poschke[1,3], Edward Green[1], Sune Justesen[10], Geoffrey A. Steinbach[19], Martin Bendszus[7], Andreas von Deimling[8,9], Michael Schmitt12 & Wolfgang Wick[4,5,20]. 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. 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. 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).
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