1. A vaccine targeting mutant IDH1 in newly diagnosed glioma.
- Author
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Platten, Michael, Bunse, Lukas, Wick, Antje, Bunse, Theresa, Le Cornet, Lucian, Harting, Inga, Sahm, Felix, Sanghvi, Khwab, Tan, Chin Leng, Poschke, Isabel, Green, Edward, Justesen, Sune, Behrens, Geoffrey A., Breckwoldt, Michael O., Freitag, Angelika, Rother, Lisa-Marie, Schmitt, Anita, Schnell, Oliver, Hense, Jörg, and Misch, Martin
- 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 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-specifcity 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 infammatory reactions. Pseudoprogression was associated with increased vaccine-induced peripheral T cell responses. Combined single-cell RNA and T cell receptor sequencing showed that tumour-infltrating CD40LG+ and CXCL13+ T helper cell clusters in a patient with pseudoprogression were dominated by a single IDH1(R132H)-reactive T cell receptor. [ABSTRACT FROM AUTHOR]- Published
- 2021
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