A vaccine targeting mutant IDH1 in newly diagnosed glioma

Michael Platten (), Lukas Bunse, Antje Wick, Theresa Bunse, Lucian Cornet, Inga Harting, Felix Sahm, Khwab Sanghvi, Chin Leng Tan, Isabel Poschke, Edward Green, Sune Justesen, Geoffrey A. Behrens, Michael O. Breckwoldt, Angelika Freitag, Lisa-Marie Rother, Anita Schmitt, Oliver Schnell, Jörg Hense, Martin Misch, Dietmar Krex, Stefan Stevanovic, Ghazaleh Tabatabai, Joachim P. Steinbach, Martin Bendszus, Andreas Deimling, Michael Schmitt and Wolfgang Wick
Additional contact information
Michael Platten: German Cancer Research Center (DKFZ)
Lukas Bunse: German Cancer Research Center (DKFZ)
Antje Wick: University of Heidelberg
Theresa Bunse: German Cancer Research Center (DKFZ)
Lucian Cornet: NCT Trial Center, NCT
Inga Harting: University of Heidelberg
Felix Sahm: DKTK CCU Neuropathology, DKFZ
Khwab Sanghvi: German Cancer Research Center (DKFZ)
Chin Leng Tan: German Cancer Research Center (DKFZ)
Isabel Poschke: German Cancer Research Center (DKFZ)
Edward Green: German Cancer Research Center (DKFZ)
Sune Justesen: Immunitrack
Geoffrey A. Behrens: DKMS Life Science Lab GmbH
Michael O. Breckwoldt: University of Heidelberg
Angelika Freitag: NCT Trial Center, NCT
Lisa-Marie Rother: NCT Trial Center, NCT
Anita Schmitt: University of Heidelberg
Oliver Schnell: University of Freiburg
Jörg Hense: University of Duisburg-Essen
Martin Misch: University of Berlin
Dietmar Krex: University of Dresden
Stefan Stevanovic: University of Tübingen
Ghazaleh Tabatabai: University of Tübingen
Joachim P. Steinbach: Dr. Senckenberg Institute of Neurooncology
Martin Bendszus: University of Heidelberg
Andreas Deimling: DKTK CCU Neuropathology, DKFZ
Michael Schmitt: University of Heidelberg
Wolfgang Wick: University of Heidelberg

Nature, 2021, vol. 592, issue 7854, 463-468

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03363-z

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