纳入CD28和TLR2细胞内结构域的第三代CD19嵌合抗原受体T细胞治疗合并中枢神经系统受累的B细胞恶性肿瘤的疗效和安全性：一项关键试验的结果

Efficacy and safety of third-generation CD19-CAR T cells incorporating CD28 and TLR2 intracellular domains for B-cell malignancies with central nervous system involvement: results of a pivotal trial.

作者信息

He Bailin, Lin Ren, Xu Na, Qin Le, Wang Zhixiang, Wang Qiang, Li Xiaofang, Wei Xiaolei, Wei Yongqiang, Tang Zhaoyang, Fan Zhiping, Huang Fen, Liu Xiaoli, Sun Jing, Xuan Li, Li Peng, Zhou Hongsheng, Liu Qifa

机构信息

Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Guangdong Provincial Clinical Research Center for Hematologic Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.

出版信息

J Transl Med. 2025 May 27;23(1):594. doi: 10.1186/s12967-025-06608-x.

DOI:10.1186/s12967-025-06608-x

PMID:40426201

Abstract

BACKGROUND

Third‑generation CAR-T cells demonstrated promising efficacy and remarkably low toxicity in refractory or relapsed (R/R) B-cell malignancies. However, data on the patients with central nervous system (CNS) involvement are limited due to concerns regarding treatment-related neurotoxicity. This study aimed to evaluate the safety and efficacy of a novel third-generation anti-CD19 CAR T cells in patients with CNS involvement of B-cell malignancies.

METHODS

A total of 21 patients with R/R B-cell malignancies with CNS involvement, including 11 with B-cell acute lymphoblastic leukemia (B-ALL) and 10 with B-cell non-Hodgkin lymphoma (B-NHL) were enrolled. Patients derived lymphocytes were collected through apheresis and lentivirally transduced with the third-generation CAR incorporating both CD28 co-stimulation and TLR2-derived stimulatory domains (1928zT2). Patients received a single-dose 1928zT2 CAR-T cell infusion following lymphodepleting regimen. Safety, efficacy and cellular pharmacokinetics were investigated.

RESULTS

Of the 21 patients with CNS involvement, the overall response rate (ORR) was 71% (15/21), with 73% (8/11) in B-ALL and 70% (7/10) in B-NHL. At a median follow-up of 20.4 months, median duration of response (DOR) was 11.1 months (95% CI, 2.9-24.4). 12-months progression-free survival (PFS) and overall survival (OS) estimates were 41.5% and 61.2%, respectively. Cytokine release syndrome (CRS) of any grade occurred in 20 patients (95%; grade ≥ 3 in 3 patients). Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 9 patients (42.8%; grade ≥ 3 in 6 patients). All CRS and ICANS events were manageable. The outcomes and adverse events are comparable between B-ALL and B-NHL patients. Notably, 1928zT2 CAR-T cells demonstrated blood-brain barrier penetrance, with subsequent detection in patient cerebrospinal fluid (CSF) correlating significantly with improved clinical outcomes.

CONCLUSIONS

Third-generation 1928zT2 CAR-T cells are associated with high response rates, manageable safety and durable remissions in R/R B-cell malignancies with CNS involvement.

TRIAL REGISTRATION

ClinicalTrials.gov, NCT04605666. Registered 1 May 2020.

摘要

背景

第三代嵌合抗原受体T细胞（CAR-T细胞）在难治性或复发性（R/R）B细胞恶性肿瘤中显示出有前景的疗效和极低的毒性。然而，由于担心治疗相关的神经毒性，关于中枢神经系统（CNS）受累患者的数据有限。本研究旨在评估新型第三代抗CD19 CAR-T细胞在B细胞恶性肿瘤CNS受累患者中的安全性和疗效。

方法

共纳入21例R/R B细胞恶性肿瘤伴CNS受累的患者，其中11例为B细胞急性淋巴细胞白血病（B-ALL），10例为B细胞非霍奇金淋巴瘤（B-NHL）。通过血细胞分离术收集患者的淋巴细胞，并用包含CD28共刺激和TLR2衍生刺激域的第三代CAR（1928zT2）进行慢病毒转导。患者在淋巴细胞清除方案后接受单剂量1928zT2 CAR-T细胞输注。研究了安全性、疗效和细胞药代动力学。

结果

在21例CNS受累患者中，总体缓解率（ORR）为71%（15/21），B-ALL患者为73%（8/11），B-NHL患者为70%（7/10）。中位随访20.4个月时，中位缓解持续时间（DOR）为11.1个月（95%CI，2.9 - 24.4）。12个月无进展生存期（PFS）和总生存期（OS）估计分别为41.5%和61.2%。20例患者（95%）发生任何级别的细胞因子释放综合征（CRS）；3例患者发生≥3级CRS。9例患者（42.8%）发生免疫效应细胞相关神经毒性综合征（ICANS）；6例患者发生≥3级ICANS。所有CRS和ICANS事件均可控。B-ALL和B-NHL患者的结局和不良事件具有可比性。值得注意的是，1928zT2 CAR-T细胞显示出可穿透血脑屏障，随后在患者脑脊液（CSF）中的检测与改善的临床结局显著相关。