In a phase I trial, patients with high-grade, IDH1-mutant astrocytomas were treated with an MHC-II-restricted IDH1 neoantigen peptide vaccine. The vaccine was safe and induced IDH1-specific CD4+ (but not CD8+) T cell responses and IDH1-binding antibodies in 26/30 patients. T cell responses correlated with baseline tumor IDH1 neoantigen levels and could stratify patient survival. The ORR was ~84% (stable disease), and a subset of patients (~38%) displayed pseudoprogression (PsPD), indicating antitumor inflammation. In one PsPD tumor analyzed by scRNAseq, infiltrating, IDH1-reactive CD4+ T cell clusters were identified, dominated by a single IDH1-reactive TCR.
Contributed by Alex Najibi
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 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 mice(4,6-8). 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.