美国西奈山医疗中心Sundar Jagannath团队研究了B细胞成熟抗原导向嵌合抗原受体T细胞治疗复发性或难治性多发性骨髓瘤的疗效。2021年6月24日出版的《柳叶刀》杂志发表了这项成果。
Ciltacabtagene autotoleucel（cilta-cel）是一种嵌合抗原受体T细胞疗法，具有两种针对单域抗体的B细胞成熟抗原，为了评估cilta-cel治疗复发或预后不良的多发性骨髓瘤患者的安全性和临床活性，研究组在美国16个中心进行了一项单臂、开放标签、1b/2期临床研究。
他们招募18岁及以上的多发性骨髓瘤患者，这些患者的东部肿瘤协作组体能状态评分为0或1，既往接受过3种及以上治疗，或对一种蛋白酶体抑制剂和一种免疫调节药物双重耐药，并接受过某种蛋白酶体抑制剂、免疫调节药物和抗CD38抗体治疗。在淋巴细胞耗竭开始后的5-7天内单次给予cilta细胞输注。主要终点是接受治疗的所有患者的安全性，确认推荐的临床2期剂量（1b期），以及临床2期的总有效率。关键次要终点是缓解持续时间和无进展生存期。
2018年7月16日至2019年10月7日，共有113例患者入组。97例患者（1b期29例，2期68例）接受了2期推荐剂量，即0.75×106个CAR阳性活T细胞/kg。截至2020年9月1日临床截止日期，中位随访时间为12.4个月。97例接受cilta-cel治疗的患者此前平均接受过6次治疗。总有效率为97%；65例（67%）患者获得严格完全缓解；首次缓解时间为1个月。缓解程度随时间推移而加深。中位缓解期未达到，无进展生存期也未达到。12个月无进展生存率为77%，总生存率为89%。
血液学不良反应很常见；3-4级血液学不良事件为中性粒细胞减少（95%）、贫血（68%）、白细胞减少（61%）、血小板减少（60%）和淋巴细胞减少（50%）。92例（95%）患者出现细胞因子释放综合征（4%为3级或4级）；中位发病时间为7.0天，中位病程为4.0天。细胞因子释放综合征除1例5级细胞因子释放综合征和噬血细胞性淋巴组织细胞增多症外，其余患者均痊愈。20例（21%）患者出现CAR-T细胞神经毒性（9%为3级或4级）。共有14例患者死亡，其中6例因治疗相关不良事件，5例因疾病进展，3例因治疗无关不良事件。
研究结果表明，对于严重预处理的多发性骨髓瘤患者，单次输注目标剂量为0.75×106个CAR阳性活T细胞/kg的cilta细胞可获得早期、深度和持久缓解，且安全性可控。
附：英文原文
Title: Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study
Author: Jesus G Berdeja, Deepu Madduri, Saad Z Usmani, Andrzej Jakubowiak, Mounzer Agha, Adam D Cohen, A Keith Stewart, Parameswaran Hari, Myo Htut, Alexander Lesokhin, Abhinav Deol, Nikhil C Munshi, Elizabeth ODonnell, David Avigan, Indrajeet Singh, Enrique Zudaire, Tzu-Min Yeh, Alicia J Allred, Yunsi Olyslager, Arnob Banerjee, Carolyn C Jackson, Jenna D Goldberg, Jordan M Schecter, William Deraedt, Sen Hong Zhuang, Jeffrey Infante, Dong Geng, Xiaoling Wu, Marlene J Carrasco-Alfonso, Muhammad Akram, Farah Hossain, Syed Rizvi, Frank Fan, Yi Lin, Thomas Martin, Sundar Jagannath
Issue&Volume: 2021-06-24
Abstract:
Background
CARTITUDE-1 aimed to assess the safety and clinical activity of ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T-cell therapy with two B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed or refractory multiple myeloma with poor prognosis.
Methods
This single-arm, open-label, phase 1b/2 study done at 16 centres in the USA enrolled patients aged 18 years or older with a diagnosis of multiple myeloma and an Eastern Cooperative Oncology Group performance status score of 0 or 1, who received 3 or more previous lines of therapy or were double-refractory to a proteasome inhibitor and an immunomodulatory drug, and had received a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. A single cilta-cel infusion (target dose 0·75×106 CAR-positive viable T cells per kg) was administered 5–7 days after start of lymphodepletion. The primary endpoints were safety and confirmation of the recommended phase 2 dose (phase 1b), and overall response rate (phase 2) in all patients who received treatment. Key secondary endpoints were duration of response and progression-free survival. This trial is registered with ClinicalTrials.gov, NCT03548207.
Findings
Between July 16, 2018, and Oct 7, 2019, 113 patients were enrolled. 97 patients (29 in phase 1b and 68 in phase 2) received a cilta-cel infusion at the recommended phase 2 dose of 0·75×106 CAR-positive viable T cells per kg. As of the Sept 1, 2020 clinical cutoff, median follow-up was 12·4 months (IQR 10·6–15·2). 97 patients with a median of six previous therapies received cilta-cel. Overall response rate was 97% (95% CI 91·2–99·4; 94 of 97 patients); 65 (67%) achieved stringent complete response; time to first response was 1 month (IQR 0·9–1·0). Responses deepened over time. Median duration of response was not reached (95% CI 15·9–not estimable), neither was progression-free survival (16·8–not estimable). The 12-month progression-free rate was 77% (95% CI 66·0–84·3) and overall survival rate was 89% (80·2–93·5). Haematological adverse events were common; grade 3–4 haematological adverse events were neutropenia (92 [95%] of 97 patients), anaemia (66 [68%]), leukopenia (59 [61%]), thrombocytopenia (58 [60%]), and lymphopenia (48 [50%]). Cytokine release syndrome occurred in 92 (95%) of 97 patients (4% were grade 3 or 4); with median time to onset of 7·0 days (IQR 5–8) and median duration of 4·0 days (IQR 3–6). Cytokine release syndrome resolved in all except one with grade 5 cytokine release syndrome and haemophagocytic lymphohistiocytosis. CAR T-cell neurotoxicity occurred in 20 (21%) patients (9% were grade 3 or 4). 14 deaths occurred in the study; six due to treatment-related adverse events, five due to progressive disease, and three due to treatment-unrelated adverse events.
Interpretation
A single cilta-cel infusion at the target dose of 0·75×106 CAR-positive viable T cells per kg led to early, deep, and durable responses in heavily pretreated patients with multiple myeloma with a manageable safety profile. The data from this study formed the basis for recent regulatory submissions.
DOI: 10.1016/S0140-6736(21)00933-8
Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00933-8/fulltext
LANCET：《柳叶刀》，创刊于1823年。隶属于爱思唯尔出版社，最新IF：202.731
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