期刊
NATURE
卷 592, 期 7854, 页码 463-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41586-021-03363-z
关键词
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资金
- German Ministry of Education and Science
- National Center for Tumor Diseases
- DKFZ Light Microscopy Facility
- DKFZ Genomics and Proteomics Core Facility
- German Ministry of Education and Science (National Center for Tumor Diseases Heidelberg NCT 3.0 program 'Precision immunotherapy of brain tumors')
- German Ministry of Education and Science 9DKTK program
- DKFZ-MOST program [2526]
- Helmholtz Program Future Topic Immunology and Inflammation [ZT-0027, WP3]
- Dr. Rolf M. Schwiete Foundation
- German Research Foundation (DFG) [FOR2289: PL315/3-1]
- Sonderforderlinie `Neuroinflammation' of the Ministry of Science of Baden Wurttemberg
- Joint Funding Program MGH-Heidelberg Alliance in Neuro-Oncology
- Wilhelm Sander Foundation [2012.118.1]
- NCT 3.0 program Cancer immunotherapy program program genetically modified cells for cancer immune therapy
- Baden-Wurttemberg Stiftung [BWST_ISF2018046]
- German Cancer Aid [70112399, 110624]
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [404521405, SFB 1389]
- epigenetics@dkfz program
- Swiss Cancer Foundation
- Else Kroner Fresenius Foundation
- University Heidelberg Foundation
- Heidelberg Medical Faculty
- Heidelberg University (Hella Buhler Award)
- Medical Faculty and University Hospital Mannheim
- University Heidelberg
- doctoral fellowship of the DKFZ
- postdoctoral fellowship of the University Hospital Heidelberg
- Marie-Curie fellowship
Mutated isocitrate dehydrogenase 1 (IDH1) defines a molecularly distinct subtype of diffuse glioma. 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 II. An IDH1(R132H)-specific peptide vaccine (IDH1-vac) induces specific therapeutic T helper cell responses that are effective against IDH1(R132H)+ tumours.
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 II(4,)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.
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