Mutated isocitrate dehydrogenase 1 (IDH1) defines a molecularly distinct subtype of diffuse glioma^1-3. 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 II^4,5. 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 mice^4,6-8. 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).

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

A vaccine targeting mutant IDH1 in newly diagnosed glioma

Michael Platten ^1 2 3, Lukas Bunse ^4 5, Antje Wick ^6 7, Theresa Bunse ^4 5, Lucian Le Cornet ⁸, Inga Harting ⁹, Felix Sahm ^10 11, Khwab Sanghvi ⁴, Chin Leng Tan ⁴, Isabel Poschke ^4 12, Edward Green ⁴, Sune Justesen ¹³, Geoffrey A Behrens ¹⁴, Michael O Breckwoldt ⁹, Angelika Freitag ⁸, Lisa-Marie Rother ⁸, Anita Schmitt ¹⁵, Oliver Schnell ¹⁶, Jörg Hense ¹⁷, Martin Misch ¹⁸, Dietmar Krex ¹⁹, Stefan Stevanovic ²⁰, Ghazaleh Tabatabai ²¹, Joachim P Steinbach ²², Martin Bendszus ⁹, Andreas von Deimling ^10 11, Michael Schmitt ¹⁵, Wolfgang Wick ^6 7 23Affiliations expand

• PMID: 33762734
• PMCID: PMC8046668
• DOI: 10.1038/s41586-021-03363-z

Free PMC article

Abstract

Mutated isocitrate dehydrogenase 1 (IDH1) defines a molecularly distinct subtype of diffuse glioma^1-3. 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 II^4,5. 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 mice^4,6-8. 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.