肿瘤细胞治疗研究
英文原题：Chimeric antigen receptor T-cell therapy targeting a MAGE A4 peptide and HLA-A*02:01 complex for unresectable advanced or recurrent solid cancer: protocol for a multi-institutional phase 1 clinical trial.
每个队列招募3名可评估受试者，总共6名受试者（最多12名受试者）将参加本临床试验。
过继性细胞转移基因工程T细胞是一种有前景的恶性肿瘤治疗方法；然而，细胞表面表达的理想肿瘤抗原很少，针对实体瘤治疗的CAR-T 细胞（CAR-T细胞）的开发一直缓慢。CAR-T细胞识别细胞表面呈递的主要组织相容性复合体和肽复合物，不仅可靶向细胞表面抗原，还可靶向细胞内抗原。我们基于临床前研究，开发了一种识别HLA-A*02:01与MAGE-A4抗原表位复合物的CAR-T细胞产品，其配备了一种新型人GITR信号结构域（研究产品代码：MU-MA402C）。 方法与分析：这是一项剂量递增、多机构、1期研究，旨在评估MU-MA402C对MAGE-A4阳性和HLA-A*02:01阳性不可切除晚期或复发性实体癌患者的耐受性和安全性。计划设两个剂量队列：队列1，MU-MA402C 2×10^8/人；队列2，MU-MA402C 2×10^9/人。在CAR-T细胞输注前，将给予环磷酰胺（CPA）和氟达拉滨（FLU）作为预处理化疗。本临床试验将每队列招募3例可评估受试者，共6例受试者（最多12例受试者）。主要终点为安全性和耐受性。各不良事件的严重程度将根据不良事件通用术语标准V.5.0进行评估。次要终点为疗效。抗肿瘤反应将根据实体瘤疗效评价标准V.1.1进行评估。 伦理与传播：本临床试验将按照现行版本的药物临床试验质量管理规范进行。该方案已获得三重大学医院临床研究伦理审查委员会的批准（批准号 F-2021-017）。试验结果将发表在同行评审期刊和/或通过国际会议传播。
INTRODUCTION: Adoptive cell transfer of genetically engineered T cells is a promising treatment for malignancies; however, there are few ideal cancer antigens expressed on the cell surface, and the development of chimeric antigen receptor T cells (CAR-T cells) for solid tumour treatment has been slow. CAR-T cells, which recognise major histocompatibility complex and peptide complexes presented on the cell surface, can be used to target not only cell surface antigens but also intracellular antigens. We have developed a CAR-T-cell product that recognises the complex of HLA-A*02:01 and an epitope of the MAGE-A4 antigen equipped with a novel signalling domain of human GITR (investigational product code: MU-MA402C) based on preclinical studies. METHODS AND ANALYSIS: This is a dose-escalation, multi-institutional, phase 1 study to evaluate the tolerability and safety of MU-MA402C for patients with MAGE A4-positive and HLA-A*02:01-positive unresectable advanced or recurrent solid cancer. Two dose cohorts are planned: cohort 1, MU-MA402C 2 10 8 /person; cohort 2, MU-MA402C 2 10 9 /person. Prior to CAR-T-cell infusion, cyclophosphamide (CPA) and fludarabine (FLU) will be administered as preconditioning chemotherapy. Three evaluable subjects per cohort, for a total of 6 subjects (maximum of 12 subjects), will be recruited for this clinical trial. The primary endpoints are safety and tolerability. The severity of each adverse event will be evaluated in accordance with Common Terminology Criteria for Adverse Events V.5.0. The secondary endpoint is efficacy. Antitumour response will be evaluated according to Response Evaluation Criteria in Solid Tumours V.1.1. ETHICS AND DISSEMINATION: This clinical trial will be conducted in accordance with the current version of Good Clinical Practice. The protocol was approved by the Clinical Research Ethics Review Committee of Mie University Hospital (approval number F-2021-017). The trial results will be published in peer-reviewed journals and/or disseminated through international conferences. TRIAL REGISTRATION NUMBER: jRCT2043210077.
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