小柯机器人

德国海德堡大学Michael Platten等研究人员报道一种靶向新诊断神经胶质瘤中突变IDH1疫苗的临床结果。相关论文于2021年3月24日在线发表于《自然》。

研究人员表示，突变的异柠檬酸脱氢酶1（IDH1）定义了弥漫性胶质瘤的分子独特亚型。胶质瘤中最常见的IDH1突变影响密码子132，并编码IDH1(R132H)，该IDH1具有共同的克隆新表位，并存在于主要组织相容性复合物（MHC）II类上。IDH1(R132H)特异性肽疫苗（IDH1-vac）诱导特异性治疗性T辅助细胞应答，该应答对同基因MHC人源化小鼠的IDH1(R132H)⁺肿瘤有效。

研究人员报道了一项多中心、单臂、开放标签、首次在人体中进行的I期临床试验，研究人员对33名新诊断出的世界卫生组织3级和4级IDH1(R132H)⁺星形细胞瘤患者进行了研究。该试验达到了其主要的安全性终点，与疫苗相关的不良事件仅限于1级。在多个MHC等位基因的93.3％的患者中观察到了疫苗诱导的免疫反应。三年的无进展率和无死亡率分别为0.63和0.84。免疫反应患者的两年无进展率为0.82。两名无免疫反应的患者在首次诊断后的两年内显示出肿瘤进展。

结合疫苗诱导的IDH1(R132H)特异性T细胞反应的持续时间和水平的突变特异性评分，与治疗前肿瘤组织中IDH1(R132H)新抗原的肿瘤内表现相关。假性进展的频率很高，表明肿瘤内炎症反应。假进展与疫苗诱导的外周T细胞应答增加有关。结合的单细胞RNA和T细胞受体测序表明，假进展的患者中，肿瘤浸润的CD40LG⁺和CXCL13⁺T辅助细胞簇由单个IDH1(R132H)反应性T细胞受体主导。

附：英文原文

Title: A vaccine targeting mutant IDH1 in newly diagnosed glioma

Author: Michael Platten, Lukas Bunse, Antje Wick, Theresa Bunse, Lucian Le Cornet, Inga Harting, Felix Sahm, Khwab Sanghvi, Chin Leng Tan, Isabel Poschke, Edward Green, Sune Justesen, Geoffrey A. Behrens, Michael O. Breckwoldt, Angelika Freitag, Lisa-Marie Rother, Anita Schmitt, Oliver Schnell, Jrg Hense, Martin Misch, Dietmar Krex, Stefan Stevanovic, Ghazaleh Tabatabai, Joachim P. Steinbach, Martin Bendszus, Andreas von Deimling, Michael Schmitt, Wolfgang Wick

Issue&Volume: 2021-03-24

Abstract: Mutated isocitrate dehydrogenase 1 (IDH1) defines a molecularly distinct subtype of diffuse glioma1,2,3. 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 II4,5. 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 mice4,6,7,8. 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.

DOI: 10.1038/s41586-021-03363-z

Source: https://www.nature.com/articles/s41586-021-03363-z

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html