A vaccine targeting mutant IDH1 in newly diagnosed glioma

Platten M, Bunse L, Wick A, Bunse T, Le Cornet L, Harting I, Sahm F, Sanghvi K, Tan CL, Poschke I, Green E, Justesen S, Behrens GA, Breckwoldt MO, Freitag A, Rother LM, Schmitt A, Schnell O, Hense J, Misch M, Krex D, Stevanovic S, Tabatabai G, Steinbach JP, Bendszus M, von Deimling A, Schmitt M, Wick W (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Nature Nature Research

Book Volume: 592

Pages Range: 463-468

Journal Issue: 7854

DOI: 10.1038/s41586-021-03363-z

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.

Authors with CRIS profile

Oliver Schnell

Involved external institutions

Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) Universitätsklinikum Heidelberg DE Germany (DE) Nationales Centrum für Tumorerkrankungen (NCT) Heidelberg DE Germany (DE) Immunitrack ApS DK Denmark (DK) DKMS Life Science Lab gGmbH DE Germany (DE) Universitätsklinikum Freiburg DE Germany (DE) Universitätsklinikum Essen DE Germany (DE) Charité - Universitätsmedizin Berlin DE Germany (DE) Universitätsklinikum Carl Gustav Carus Dresden DE Germany (DE) Eberhard Karls Universität Tübingen DE Germany (DE) Senckenberg Forschungsinstitut und Naturmuseum DE Germany (DE)

How to cite

APA:

Platten, M., Bunse, L., Wick, A., Bunse, T., Le Cornet, L., Harting, I.,... Wick, W. (2021). A vaccine targeting mutant IDH1 in newly diagnosed glioma. Nature, 592(7854), 463-468. https://doi.org/10.1038/s41586-021-03363-z

MLA:

Platten, Michael, et al. "A vaccine targeting mutant IDH1 in newly diagnosed glioma." Nature 592.7854 (2021): 463-468.

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