Back to Search
Start Over
A vaccine targeting mutant IDH1 in newly diagnosed glioma.
- Source :
-
Nature [Nature] 2021 Apr; Vol. 592 (7854), pp. 463-468. Date of Electronic Publication: 2021 Mar 24. - Publication Year :
- 2021
-
Abstract
- Mutated isocitrate dehydrogenase 1 (IDH1) defines a molecularly distinct subtype of diffuse glioma <superscript>1-3</superscript> . 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 <superscript>4,5</superscript> . An IDH1(R132H)-specific peptide vaccine (IDH1-vac) induces specific therapeutic T helper cell responses that are effective against IDH1(R132H) <superscript>+</superscript> tumours in syngeneic MHC-humanized mice <superscript>4,6-8</superscript> . 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) <superscript>+</superscript> 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 <superscript>+</superscript> and CXCL13 <superscript>+</superscript> T helper cell clusters in a patient with pseudoprogression were dominated by a single IDH1(R132H)-reactive T cell receptor.
- Subjects :
- Adult
Cells, Cultured
Disease Progression
Female
Glioma genetics
Glioma immunology
Humans
Male
Mutant Proteins genetics
Mutant Proteins immunology
Phenotype
Receptors, Antigen, T-Cell immunology
Survival Rate
T-Lymphocytes immunology
Cancer Vaccines immunology
Cancer Vaccines therapeutic use
Glioma diagnosis
Glioma therapy
Isocitrate Dehydrogenase genetics
Isocitrate Dehydrogenase immunology
Mutation
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 592
- Issue :
- 7854
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 33762734
- Full Text :
- https://doi.org/10.1038/s41586-021-03363-z