AMPLIFY-NEOVAC：一项随机、三臂多中心I期试验，旨在评估异柠檬酸脱氢酶1（IDH1）疫苗联合靶向程序性死亡配体1的免疫检查点抑制剂在IDH1突变型胶质瘤中的安全性、耐受性和免疫原性。
AMPLIFY-NEOVAC: a randomized, 3-arm multicenter phase I trial to assess safety, tolerability and immunogenicity of IDH1-vac combined with an immune checkpoint inhibitor targeting programmed death-ligand 1 in isocitrate dehydrogenase 1 mutant gliomas.
作者信息
Bunse Lukas, Rupp Anne-Kathleen, Poschke Isabel, Bunse Theresa, Lindner Katharina, Wick Antje, Blobner Jens, Misch Martin, Tabatabai Ghazaleh, Glas Martin, Schnell Oliver, Gempt Jens, Denk Monika, Reifenberger Guido, Bendszus Martin, Wuchter Patrick, Steinbach Joachim P, Wick Wolfgang, Platten Michael
机构信息
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.
出版信息
Neurol Res Pract. 2022 May 23;4(1):20. doi: 10.1186/s42466-022-00184-x.
INTRODUCTION
Isocitrate dehydrogenase (IDH) mutations are disease-defining mutations in IDH-mutant astrocytomas and IDH-mutant and 1p/19q-codeleted oligodendrogliomas. In more than 80% of these tumors, point mutations in IDH type 1 (IDH1) lead to expression of the tumor-specific protein IDH1R132H. IDH1R132H harbors a major histocompatibility complex class II (MHCII)-restricted neoantigen that was safely and successfully targeted in a first-in human clinical phase 1 trial evaluating an IDH1R132H 20-mer peptide vaccine (IDH1-vac) in newly diagnosed astrocytomas concomitant to standard of care (SOC).
METHODS
AMPLIFY-NEOVAC is a randomized, 3-arm, window-of-opportunity, multicenter national phase 1 trial to assess safety, tolerability and immunogenicity of IDH1-vac combined with avelumab (AVE), an immune checkpoint inhibitor (ICI) targeting programmed death-ligand 1 (PD-L1). The target population includes patients with resectable IDH1R132H-mutant recurrent astrocytoma or oligodendroglioma after SOC. Neoadjuvant and adjuvant immunotherapy will be administered to 48 evaluable patients. In arm 1, 12 patients will receive IDH1-vac; in arm 2, 12 patients will receive the combination of IDH1-vac and AVE, and in arm 3, 24 patients will receive AVE only. Until disease progression according to immunotherapy response assessment for neuro-oncology (iRANO) criteria, treatment will be administered over a period of maximum 43 weeks (primary treatment phase) followed by facultative maintenance treatment.
PERSPECTIVE
IDH1R132H 20-mer peptide is a shared clonal driver mutation-derived neoepitope in diffuse gliomas. IDH1-vac safely targets IDH1R132H in newly diagnosed astrocytomas. AMPLIFY-NEOVAC aims at (1) demonstrating safety of enhanced peripheral IDH1-vac-induced T cell responses by combined therapy with AVE compared to IDH1-vac only and (2) investigating intra-glioma abundance and phenotypes of IDH1-vac induced T cells in exploratory post-treatment tissue analyses. In an exploratory analysis, both will be correlated with clinical outcome.
TRIAL REGISTRATION
NCT03893903.
引言
异柠檬酸脱氢酶（IDH）突变是IDH突变型星形细胞瘤以及IDH突变型且1p/19q共缺失型少突胶质细胞瘤的疾病定义性突变。在超过80%的这类肿瘤中，IDH1型（IDH1）的点突变导致肿瘤特异性蛋白IDH1R132H的表达。IDH1R132H含有一种主要组织相容性复合体II类（MHCII）限制性新抗原，在一项针对新诊断星形细胞瘤的首次人体临床1期试验中，该新抗原被安全且成功地作为靶点，该试验将IDH1R132H 20肽疫苗（IDH1-vac）与标准治疗（SOC）联合应用。
方法
AMPLIFY-NEOVAC是一项随机、三臂、机会窗、多中心全国性1期试验，旨在评估IDH1-vac与阿维鲁单抗（AVE）联合应用的安全性、耐受性和免疫原性，阿维鲁单抗是一种靶向程序性死亡配体1（PD-L1）的免疫检查点抑制剂（ICI）。目标人群包括在接受SOC后可切除的IDH1R132H突变型复发性星形细胞瘤或少突胶质细胞瘤患者。新辅助和辅助免疫治疗将给予48例可评估患者。在第1组中，12例患者将接受IDH1-vac；在第2组中，12例患者将接受IDH1-vac与AVE的联合治疗，在第3组中，24例患者将仅接受AVE治疗。根据神经肿瘤免疫治疗反应评估（iRANO）标准，直到疾病进展，治疗将在最长43周的时间内进行（主要治疗阶段），随后进行选择性维持治疗。
展望
IDH1R132H 20肽是弥漫性胶质瘤中一种共同的克隆驱动突变衍生的新表位。IDH1-vac在新诊断的星形细胞瘤中安全地靶向IDH1R132H。AMPLIFY-NEOVAC旨在（1）证明与仅使用IDH1-vac相比，通过与AVE联合治疗增强外周IDH1-vac诱导的T细胞反应的安全性，以及（2）在探索性治疗后组织分析中研究IDH1-vac诱导的T细胞在胶质瘤内的丰度和表型。在探索性分析中，两者都将与临床结果相关联。
试验注册
NCT03893903。
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