Journal Article

DKFZ-2021-00721

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A vaccine targeting mutant IDH1 in newly diagnosed glioma.

Platten, M. (First author)DKFZ* ; Bunse, L.DKFZ* ; Wick, A. ; Bunse, T.DKFZ* ; Le Cornet, L. ; Harting, I. ; Sahm, F.DKFZ* ; Sanghvi, K.DKFZ* ; Tan, C. L.DKFZ* ; Poschke, I.DKFZ* ; Green, E.DKFZ* ; Justesen, S. ; Behrens, G. A. ; Breckwoldt, M. O. ; Freitag, A. ; Rother, L.-M. ; Schmitt, A. ; Schnell, O. ; Hense, J. ; Misch, M. ; Krex, D. ; Stevanovic, S. ; Tabatabai, G. ; Steinbach, J. P. ; Bendszus, M. ; von Deimling, A.DKFZ* ; Schmitt, M. ; Wick, W.DKFZ*

2021
Nature Publ. Group52462 London [u.a.]

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Please use a persistent id in citations: 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.

Note: #EA:D170#LA:B320# /592(7854):463-468 / #DKFZ-MOST-Ca188#

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Contributing Institute(s):

1. KKE Neuroimmunologie und Hirntumorimmunologie (D170)
2. DKTK HD zentral (HD01)
3. KKE Neuropathologie (B300)
4. KKE Neuroonkologie (B320)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2021

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