肿瘤细胞治疗研究
英文原题：CYAD-01, an autologous NKG2D-based CAR T-cell therapy, in relapsed or refractory acute myeloid leukaemia and myelodysplastic syndromes or multiple myeloma (THINK): haematological cohorts of the dose escalation segment of a phase 1 trial.
采用无预处理的多剂 CYAD-01 输注方案治疗耐受性良好并显示出抗白血病活性，但在桥接至异基因 HSCT 的患者之外缺乏持久性。
背景：CYAD-01是一种基于自然杀伤（NK）组2D（NKG2D）受体的自体嵌合抗原受体（CAR）T细胞产品。NKG2D结合8种配体，这些配体在多种血液系统恶性肿瘤中过表达，而在非肿瘤细胞中基本不存在。早期临床评估显示，对复发或难治性急性髓系白血病、骨髓增生异常综合征和多发性骨髓瘤患者低剂量单次输注CYAD-01具有可行性，因此进一步评估CYAD-01。本研究旨在确定无需预处理或桥接化疗而给予CYAD-01的安全性及推荐II期剂量。方法：多中心THINK研究是一项开放标签剂量递增I期研究，纳入至少接受过一线治疗的复发或难治性急性髓系白血病、骨髓增生异常综合征或多发性骨髓瘤患者。患者来自美国和比利时的5家医院。剂量递增阶段评估三个剂量：每次输注3×10⁸细胞（剂量水平1）、1×10⁹细胞（水平2）和3×10⁹细胞（水平3），采用3+3 Fibonacci设计；每2周输注一次，共3次，之后可能接受巩固治疗，再输注3次。所有接受治疗患者中CYAD-01输注后剂量限制性毒性发生情况为主要终点。试验注册号：ClinicalTrials.gov NCT03018405和EudraCT 2016-003312-12。试验已完成。结果：2017年2月6日至2018年10月9日，血液系统疾病剂量递增部分登记25名患者。7名因产量不足而制备失败，2名筛查失败。16名患者接受CYAD-01治疗（剂量水平1：多发性骨髓瘤3名、急性髓系白血病3名；水平2：急性髓系白血病3名；水平3：急性髓系白血病6名、骨髓增生异常综合征1名）。中位随访118天（四分位距46–180天）。7名患者（44%）出现3或4级治疗相关不良事件。所有剂量水平中共有5名患者（31%）发生3或4级CRS。剂量水平3报告1例CRS剂量限制性毒性。无治疗相关死亡，且未达到最大耐受剂量。12名复发/难治性急性髓系白血病或骨髓增生异常综合征可评估患者中，3名（25%）获得客观缓解。应答者中，2名急性髓系白血病患者接受CYAD-01后进一步接受异基因造血干细胞移植（HSCT），并持续缓解（5个月和61个月）。解释：无需预处理的多次CYAD-01输注方案耐受性良好，显示抗白血病活性，但除桥接至异基因HSCT的患者外，缓解不持久。这些I期数据支持CAR T细胞靶向NKG2D配体的概念验证。值得进一步开展NKG2D CAR T细胞临床研究，或采用联合抗原靶向策略提高抗肿瘤活性。经费来源：Celyad Oncology。
BACKGROUND: CYAD-01 is an autologous chimeric antigen receptor (CAR) T-cell product based on the natural killer (NK) group 2D (NKG2D) receptor, which binds eight ligands that are overexpressed in a wide range of haematological malignancies but are largely absent on non-neoplastic cells. Initial clinical evaluation of a single infusion of CYAD-01 at a low dose in patients with relapsed or refractory acute myeloid leukaemia, myelodysplastic syndromes, and multiple myeloma supported the feasibility of the approach and prompted further evaluation of CYAD-01. The aim of the present study was to determine the safety and recommended phase 2 dosing of CYAD-01 administered without preconditioning or bridging chemotherapy. METHODS: The multicentre THINK study was an open-label, dose-escalation, phase 1 study for patients with relapsed or refractory acute myeloid leukaemia, myelodysplastic syndromes, or multiple myeloma, after at least one previous line of therapy. Patients were recruited from five hospitals in the USA and Belgium. The dose-escalation segment evaluated three dose levels: 3 10 8 (dose level one), 1 10 9 (dose level two), and 3 10 9 (dose level three) cells per infusion with a 3 + 3 Fibonacci study design using a schedule of three infusions at 2-week intervals followed by potential consolidation treatment consisting of three additional infusions. The occurrence of dose-limiting toxicities post-CYAD-01 infusion was assessed as the primary endpoint in the total treated patient population. The trial was registered with ClinicalTrials.gov, NCT03018405, and EudraCT, 2016-003312-12, and has been completed. FINDINGS: Between Feb 6, 2017, and Oct 9, 2018, 25 patients were registered in the haematological dose-escalation segment. Seven patients had manufacturing failure for insufficient yield and two had screening failure. 16 patients were treated with CYAD-01 (three with multiple myeloma and three with acute myeloid leukaemia at dose level one; three with acute myeloid leukaemia at dose level two; and six with acute myeloid leukaemia and one with myelodysplastic syndromes at dose level three). Median follow-up was 118 days (IQR 46-180). Seven patients (44%) had grade 3 or 4 treatment-related adverse events. In total, five patients (31%) had grade 3 or 4 cytokine release syndrome across all dose levels. One dose-limiting toxicity of cytokine release syndrome was reported at dose level three. No treatment-related deaths occurred, and the maximum tolerated dose was not reached. Three (25%) of 12 evaluable patients with relapsed or refractory acute myeloid leukaemia or myelodysplastic syndromes had an objective response. Among responders, two patients with acute myeloid leukaemia proceeded to allogeneic haematopoietic stem-cell transplantation (HSCT) after CYAD-01 treatment, with durable ongoing remissions (5 and 61 months). INTERPRETATION: Treatment with a multiple CYAD-01 infusion schedule without preconditioning is well tolerated and shows anti-leukaemic activity, although without durability outside of patients bridged to allogeneic HSCT. These phase 1 data support the proof-of-concept of targeting NKG2D ligands by CAR T-cell therapy. Further clinical studies with NKG2D-based CAR T-cells are warranted, potentially via combinatorial antigen targeted approaches, to improve anti-tumour activity. FUNDING: Celyad Oncology.
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