A vaccine targeting mutant IDH1 induces antitumour immunity - PubMed (original) (raw)
. 2014 Aug 21;512(7514):324-7.
doi: 10.1038/nature13387. Epub 2014 Jun 25.
Lukas Bunse 1, Stefan Pusch 2, Felix Sahm 2, Benedikt Wiestler 3, Jasmin Quandt 4, Oliver Menn 5, Matthias Osswald 3, Iris Oezen 6, Martina Ott 6, Melanie Keil 6, Jörg Balß 7, Katharina Rauschenbach 6, Agnieszka K Grabowska 8, Isabel Vogler 9, Jan Diekmann 10, Nico Trautwein 11, Stefan B Eichmüller 4, Jürgen Okun 12, Stefan Stevanović 11, Angelika B Riemer 8, Ugur Sahin 10, Manuel A Friese 13, Philipp Beckhove 4, Andreas von Deimling 2, Wolfgang Wick 3, Michael Platten 6
Affiliations
- PMID: 25043048
- DOI: 10.1038/nature13387
A vaccine targeting mutant IDH1 induces antitumour immunity
Theresa Schumacher et al. Nature. 2014.
Abstract
Monoallelic point mutations of isocitrate dehydrogenase type 1 (IDH1) are an early and defining event in the development of a subgroup of gliomas and other types of tumour. They almost uniformly occur in the critical arginine residue (Arg 132) in the catalytic pocket, resulting in a neomorphic enzymatic function, production of the oncometabolite 2-hydroxyglutarate (2-HG), genomic hypermethylation, genetic instability and malignant transformation. More than 70% of diffuse grade II and grade III gliomas carry the most frequent mutation, IDH1(R132H) (ref. 3). From an immunological perspective, IDH1(R132H) represents a potential target for immunotherapy as it is a tumour-specific potential neoantigen with high uniformity and penetrance expressed in all tumour cells. Here we demonstrate that IDH1(R132H) contains an immunogenic epitope suitable for mutation-specific vaccination. Peptides encompassing the mutated region are presented on major histocompatibility complexes (MHC) class II and induce mutation-specific CD4(+) T-helper-1 (TH1) responses. CD4(+) TH1 cells and antibodies spontaneously occurring in patients with IDH1(R132H)-mutated gliomas specifically recognize IDH1(R132H). Peptide vaccination of mice devoid of mouse MHC and transgenic for human MHC class I and II with IDH1(R132H) p123-142 results in an effective MHC class II-restricted mutation-specific antitumour immune response and control of pre-established syngeneic IDH1(R132H)-expressing tumours in a CD4(+) T-cell-dependent manner. As IDH1(R132H) is present in all tumour cells of these slow-growing gliomas, a mutation-specific anti-IDH1(R132H) vaccine may represent a viable novel therapeutic strategy for IDH1(R132H)-mutated tumours.
Comment in
- Neuro-oncology: Mice vaccinated against tumour recurrence.
Malkki H. Malkki H. Nat Rev Neurol. 2014 Aug;10(8):428. doi: 10.1038/nrneurol.2014.124. Epub 2014 Jul 8. Nat Rev Neurol. 2014. PMID: 25002106 No abstract available. - Mutant IDH1 is an effective immunotherapeutic target for glioma.
[No authors listed] [No authors listed] Cancer Discov. 2014 Sep;4(9):OF13. doi: 10.1158/2159-8290.CD-RW2014-145. Epub 2014 Jul 9. Cancer Discov. 2014. PMID: 25185195 - Immunotherapy for secondary glioblastoma multiforme: toward an isocitrate dehydrogenase vaccine.
Abecassis IJ, Morton RP, Nerva JD, Kim LJ. Abecassis IJ, et al. World Neurosurg. 2014 Dec;82(6):933-5. doi: 10.1016/j.wneu.2014.10.006. Epub 2014 Oct 13. World Neurosurg. 2014. PMID: 25311977 No abstract available.
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