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.
Author Info: (1) DKTK (German Cancer Consortium) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. m.platten
Author Info: (1) DKTK (German Cancer Consortium) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. m.platten@dkfz.de. Department of Neurology, Medical Faculty Mannheim, MCTN, University of Heidelberg, Mannheim, Germany. m.platten@dkfz.de. Immune Monitoring Unit, National Center for Tumor Diseases (NCT), Heidelberg, Germany. m.platten@dkfz.de. (2) DKTK (German Cancer Consortium) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, MCTN, University of Heidelberg, Mannheim, Germany. (3) Neurology Clinic, Heidelberg University Hospital, University of Heidelberg, Heidelberg, Germany. NCT, Heidelberg, Germany. (4) DKTK (German Cancer Consortium) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, MCTN, University of Heidelberg, Mannheim, Germany. (5) NCT Trial Center, NCT, Heidelberg, Germany. (6) Department of Neuroradiology, Heidelberg University Hospital, University of Heidelberg, Heidelberg, Germany. (7) DKTK CCU Neuropathology, DKFZ, Heidelberg, Germany. Department of Neuropathology, Heidelberg University Hospital, University of Heidelberg, Heidelberg, Germany. (8) DKTK (German Cancer Consortium) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. (9) DKTK (German Cancer Consortium) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. (10) DKTK (German Cancer Consortium) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Immune Monitoring Unit, National Center for Tumor Diseases (NCT), Heidelberg, Germany. (11) DKTK (German Cancer Consortium) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. (12) Immunitrack, Copenhagen, Denmark. (13) DKMS Life Science Lab GmbH, Dresden, Germany. (14) Department of Neuroradiology, Heidelberg University Hospital, University of Heidelberg, Heidelberg, Germany. (15) NCT Trial Center, NCT, Heidelberg, Germany. (16) NCT Trial Center, NCT, Heidelberg, Germany. (17) Department of Internal Medicine V, Heidelberg University Hospital, University of Heidelberg, Heidelberg, Germany. (18) Department of Neurosurgery, University of Freiburg, Freiburg, Germany. (19) Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. (20) Department of Neurosurgery, Charit Medical Center, University of Berlin, Berlin, Germany. (21) Department of Neurosurgery, Carl Gustav Carus University Hospital, University of Dresden, Dresden, Germany. (22) Institute of Cell Biology, Department of Immunology, University of Tbingen, Tbingen, Germany. (23) Department of Neurology, University of Tbingen, Tbingen, Germany. (24) Dr. Senckenberg Institute of Neurooncology, Frankfurt, Germany. (25) Department of Neuroradiology, Heidelberg University Hospital, University of Heidelberg, Heidelberg, Germany. (26) DKTK CCU Neuropathology, DKFZ, Heidelberg, Germany. Department of Neuropathology, Heidelberg University Hospital, University of Heidelberg, Heidelberg, Germany. (27) Department of Internal Medicine V, Heidelberg University Hospital, University of Heidelberg, Heidelberg, Germany. (28) Neurology Clinic, Heidelberg University Hospital, University of Heidelberg, Heidelberg, Germany. NCT, Heidelberg, Germany. DKTK CCU Neurooncology, DKFZ, Heidelberg, Germany.
