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Mutated isocitrate dehydrogenase 1 (IDH1) defines a molecularly distinct subtype of diffuse glioma.sup.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.sup.4,5. An IDH1(R132H)-specific peptide vaccine (IDH1-vac) induces specific therapeutic T helper cell responses that are effective against IDH1(R132H).sup.+ tumours in syngeneic MHC-humanized mice.sup.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).sup.+ 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.sup.+ and CXCL13.sup.+ T helper cell clusters in a patient with pseudoprogression were dominated by a single IDH1(R132H)-reactive T cell receptor. A phase 1 clinical trial provides evidence that a vaccine against mutant IDH1 is safe and produces a T helper immune response in patients with glioma., Author(s): Michael Platten [sup.1] [sup.2] [sup.3] , Lukas Bunse [sup.1] [sup.2] , Antje Wick [sup.4] [sup.5] , Theresa Bunse [sup.1] [sup.2] , Lucian Le Cornet [sup.6] , Inga Harting [sup.7] [...]

Purpose: Gliomas are intrinsic brain tumors with a high degree of constitutive and acquired resistance to standard therapeutic modalities such as radiotherapy and alkylating chemotherapy. Glioma subtypes are recognized by characteristic mutations. Some of these characteristic mutations have shown to generate immunogenic neoepitopes suitable for targeted immunotherapy., Experimental Design: Using peptide-based ELISpot assays, we screened for potential recurrent glioma neoepitopes in MHC-humanized mice. Following vaccination, droplet-based single-cell T-cell receptor (TCR) sequencing from established T-cell lines was applied for neoepitope-specific TCR discovery. Efficacy of intraventricular TCR-transgenic T-cell therapy was assessed in a newly developed glioma model in MHC-humanized mice induced by CRISPR-based delivery of tumor suppressor-targeting guide RNAs., Results: We identify recurrent capicua transcriptional repressor (CIC) inactivating hotspot mutations at position 215 CICR215W/Q as immunogenic MHC class II (MHCII)-restricted neoepitopes. Vaccination of MHC-humanized mice resulted in the generation of robust MHCII-restricted mutation-specific T-cell responses against CICR215W/Q. Adoptive intraventricular transfer of CICR215W-specific TCR-transgenic T cells exert antitumor responses against CICR215W-expressing syngeneic gliomas., Conclusions: The integration of immunocompetent MHC-humanized orthotopic glioma models in the discovery of shared immunogenic glioma neoepitopes facilitates the identification and preclinical testing of human leukocyte antigen (HLA)-restricted neoepitope-specific TCRs for locoregional TCR-transgenic T-cell adoptive therapy., (©2021 The Authors; Published by the American Association for Cancer Research.)

The speed of T cell receptor (TCR) discovery has been revolutionized by barcode-based TCR sequencing approaches that allow the reconstitution of a T cell's paired alpha and beta TCR chain, and the process of TCR discovery promises to become ever faster and cheaper with the continuing development single cell analysis techniques. This technological progress has generated an urgent need to develop efficient TCR validation platforms for the rapid and safe clinical translation of TCRs into therapeutic agents. Whereas much attention has in the past focused on CD8-positive cytotoxic T cells recognizing MHC class I presented epitopes, the increasing demand to validate TCRs expressed on neoepitope-reactive CD4 T cells requires the implementation of large-scale T cell activation-based readout assays to complement existing multimer and cytotoxicity-based assays. Here, we present commonly used TCR validation assays, and include detailed guidance on TCR synthesis, delivery, and appropriate experimental control TCRs. We also comment on upcoming methods that hold promise for further speeding the process of TCR validation, hastening the translation of TCRs from the laboratory into the clinic., (© 2019 Elsevier Inc. All rights reserved.)