肿瘤细胞治疗研究
英文原题：IL-10-expressing, anti-CD19 CAR T cells for patients with relapsed or refractory B-cell acute lymphoblastic leukaemia: an open-label, single-arm, phase 1 study.
IL-10-expressing, anti-CD19 CAR T cells for patients with relapsed or refractory B-cell acute lymphoblastic leukaemia: an open-label, single-arm, phase 1 study.
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META 10-19 在低剂量下对复发/难治性 B 细胞急性淋巴细胞白血病患者显示出可控的安全性特征和良好的抗白血病活性，突显了 IL-10 工程化是优化该患者群体 CAR-T 细胞治疗的潜在策略。
嵌合抗原受体（CAR）T细胞疗法改善了复发/难治性B细胞急性淋巴细胞白血病患者的临床结局，但CAR-T 细胞功能障碍所致的治疗耐药以及缓解后复发仍是重要临床挑战。为减轻这一局限，研究者开发了表达IL-10的抗CD19 CAR-T 细胞（META 10-19），并评估其在该患者群体中的安全性和活性。
研究者在中国合肥中国科学技术大学附属第一医院开展了一项开放标签、单臂、I期研究。纳入年龄3至70岁、依据世界卫生组织《造血与淋巴组织肿瘤分类》第5版确诊为复发/难治性B细胞急性淋巴细胞白血病，且东部肿瘤协作组体能状态评分为0–1分的患者。第-5至-3天静脉给予氟达拉滨（每日25–30 mg/m²）和环磷酰胺（每日250–300 mg/m²）进行淋巴细胞清除。随后单次静脉输注META 10-19，剂量为每千克体重0.1×10^6或0.2×10^6个CAR-T 细胞。主要终点为安全性（通过剂量限制性毒性、免疫效应细胞相关毒性及其他治疗相关不良事件评估）和活性（通过临床缓解率及生存评估）。安全性和活性分析纳入所有符合条件并接受META 10-19输注的患者。本研究已完成，并在ClinicalTrials.gov注册，编号NCT05747157。
2023年5月16日至2024年7月29日，15例患者入组并采集全血。12例患者（年龄中位数48岁，四分位距33–53岁）接受META 10-19输注并纳入分析；均为中国人，其中男性7例（58%）、女性5例（42%）。中位随访时间为12.5个月（四分位距7.4–15.6）。最常见的3级及以上不良事件为血液学毒性，12例患者均发生（100%），包括中性粒细胞减少（12例，100%）、贫血（10例，83%）和血小板减少（10例，83%）。11例（92%）患者发生1或2级细胞因子释放综合征；无人发生免疫效应细胞相关神经毒性综合征。未报告治疗相关死亡。输注后1个月，12例患者均有总体应答（100%），其中完全缓解4例（33%）、完全缓解但血液学恢复不完全或部分恢复5例（42%），形态学白血病未检出状态3例（25%）。解读：低剂量META 10-19用于复发/难治性B细胞急性淋巴细胞白血病患者时，安全性可控且显示出良好的抗白血病活性，提示IL-10工程化可能成为优化该患者群体CAR-T 细胞治疗的一种策略。经费来源：中国合肥综合性国家科学中心健康与医学研究院领军医学与先进技术中心、国家自然科学基金、深圳市科技计划及合肥市自然科学基金。摘要中文译文见补充材料部分。
Although chimeric antigen receptor (CAR) T-cell therapy has improved clinical outcomes for patients with relapsed or refractory B-cell acute lymphoblastic leukaemia, treatment resistance and relapse after remission driven by CAR T-cell dysfunction remain significant clinical challenges. To mitigate this limitation, we developed anti-CD19 CAR T cells expressing IL-10 (META 10-19) and aimed to assess their safety and activity in this patient group.
We conducted an open-label, single-arm, phase 1 study at the First Affiliated Hospital of University of Science and Technology of China, Hefei, China. Patients aged 3-70 years with relapsed or refractory B-cell acute lymphoblastic leukaemia diagnosed according to the 5th edition of WHO's Classification of Haematolymphoid Tumours and an Eastern Cooperative Oncology Group performance status score of 0-1 were eligible for inclusion. Lymphodepletion was achieved by use of intravenous fludarabine (25-30 mg/m 2 per day) and intravenous cyclophosphamide (250-300 mg/m 2 per day) from day -5 to -3. META 10-19 was administered intravenously in a single infusion of 0 1 10 6 or 0 2 10 6 CAR T cells per kg. The primary endpoints were safety, assessed by dose-limiting toxicity, immune effector cell-associated toxicity, and other treatment-related adverse events; and activity, assessed by clinical response rate and survival. Safety and activity were analysed in all eligible patients who received META 10-19 infusion. This study is registered with ClinicalTrials.gov, NCT05747157, and has been completed.
Between May 16, 2023, and July 29, 2024, 15 patients were enrolled and underwent whole-blood collection. 12 patients (median age 48 years [IQR 33-53]) received META 10-19 infusion and were included in the analyses, of whom all patients were Chinese, seven (58%) were men, and five (42%) were women. Median follow-up was 12 5 months (IQR 7 4-15 6). The most common grade 3 or worse adverse events were haematological toxicities in all 12 (100%) patients, including neutropenia (12 [100%]), anaemia (ten [83%]), and thrombocytopenia (ten [83%]). 11 (92%) patients had grade 1 or 2 cytokine release syndrome; no patients experienced immune effector cell-associated neurotoxicity syndrome. No treatment-related deaths were reported. Overall response at 1 month was observed in all 12 (100%) patients, with complete response in four (33%) patients, complete response with incomplete or partial haematological recovery in five (42%) patients, and morphological leukaemia-free state in three (25%) patients. INTERPRETATION: META 10-19 showed a manageable safety profile and promising antileukaemic activity in patients with relapsed or refractory B-cell acute lymphoblastic leukaemia at low doses, highlighting that IL-10 engineering is a potential strategy for optimising CAR T-cell therapy in this patient group. FUNDING: Centre for Leading Medicine and Advanced Technologies of Institute of Health and Medicine, Hefei Comprehensive National Science Center, National Natural Science Foundation of China, Shenzhen Science and Technology Program, and Hefei Municipal Natural Science Foundation. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
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