在接受鼠源 CD19 CAR-T 治疗后复发或失败的复发/难治性 B-ALL 患者中使用人源化 CD19 CAR-T 细胞。
Humanized CD19 CAR-T cells in relapsed/refractory B-ALL patients who relapsed after or failed murine CD19 CAR-T therapy.
机构信息
Department of Hematology, Beijing Boren Hospital, No.6 South Zhengwangfen, Fengtai District, Beijing, 100070, China.
Cytology Laboratory, Beijing Boren Hospital, Beijing, China.
出版信息
BMC Cancer. 2022 Apr 12;22(1):393. doi: 10.1186/s12885-022-09489-1.
BACKGROUND
For CD19-positive relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) after treatment with murine CD19 (mCD19) CAR-T, the reinfusion of mCD19 CAR-T cells may be ineffective due to anti-mouse single-chain variable fragment (scFv) antibody caused by mCD19 CAR. To overcome this immunogenicity, we applied humanized CD19 (hCD19) CAR-T cells to treat r/r B-ALL patients with prior mCD19 CAR-T therapy.
METHODS
Nineteen pediatric and adult patients were included, 16 relapsed after and 3 were primarily resistant to mCD19 CAR-T. All patients presented with more than 5% blasts in bone marrow and/or extramedullary disease, and still showed CD19 antigen expression. Humanized CD19-CARs were lentiviral vectors carrying a second generation CAR with 4-1-BB co-stimulatory and CD3ζ signaling domains. Patient-derived cells were collected for producing CAR-T cells, the median dose of infused hCD19 CAR-T cells was 2.4 × 10/kg (range, 1.0-18.0 × 10/kg).
RESULTS
hCD19 CAR-T resulted in a complete remission (CR) rate of 68% (13/19). Among 13 remission patients, 11 underwent allogeneic hematopoietic cell transplantation (allo-HCT) (3 were second HCT) and 10 remained in CR; the event-free survival rates at 12-18 months were 91% in 11 patients received following allo-HCT and 69% in all CR patients. Six cases had no response to hCD19 CAR-T, 3 died of disease progression; another 3 received salvage second transplantation, of them, 2 relapsed again (one died). Cytokine release syndrome (CRS) occurred in 95% (18/19) of patients, most CRS events were grade 1 and grade 2 (n = 17), there was only one grade 4 CRS. Two cases experienced grade 1 neurotoxicity.
CONCLUSIONS
Humanized CD19 CAR-T cell therapy could be a treatment option for CD19-positive B-ALL patients who relapsed after or resisted prior murine CD19 CAR-T, hCD19 CAR-T followed by allo-HCT provided a longer remission in CR patients. Nevertheless, the prognosis of non-responders to hCD19 CAR-T remained dismal.
TRIAL REGISTRATION
Chinese Clinical Trial Registry/WHO International Clinical Trial Registry ( ChiCTR1900024456 , URL: www.chictr.org.cn ); registered on July 12, 2019.
背景
对于接受鼠源 CD19（mCD19）嵌合抗原受体 T（CAR-T）治疗后复发/难治性 B 细胞急性淋巴细胞白血病（r/r B-ALL）患者，由于 mCD19 CAR 引发的抗鼠单链可变片段（scFv）抗体，再次输注 mCD19 CAR-T 细胞可能无效。为了克服这种免疫原性，我们应用人源化 CD19（hCD19）CAR-T 细胞治疗既往接受过 mCD19 CAR-T 治疗的 r/r B-ALL 患者。
方法
纳入 19 例儿科和成年患者，16 例在 mCD19 CAR-T 后复发，3 例为原发性耐药。所有患者骨髓和/或髓外疾病中均有超过 5%的blasts，且仍表现出 CD19 抗原表达。人源化 CD19-CAR 是携带第二代 CAR 的慢病毒载体，具有 4-1-BB 共刺激和 CD3ζ 信号结构域。从患者中采集细胞用于产生 CAR-T 细胞，输注的 hCD19 CAR-T 细胞中位数剂量为 2.4×106/kg（范围，1.0-18.0×106/kg）。
结果
hCD19 CAR-T 导致完全缓解（CR）率为 68%（13/19）。在 13 例缓解患者中，11 例接受异基因造血细胞移植（allo-HCT）（3 例为第二次 HCT），10 例仍处于 CR 状态；11 例接受后续 allo-HCT 的患者 12-18 个月时无事件生存率为 91%，所有 CR 患者为 69%。6 例对 hCD19 CAR-T 无反应，3 例死于疾病进展；另外 3 例接受挽救性二次移植，其中 2 例再次复发（1 例死亡）。95%（18/19）的患者发生细胞因子释放综合征（CRS），大多数 CRS 事件为 1 级和 2 级（n=17），仅 1 例为 4 级 CRS。2 例发生 1 级神经毒性。
结论
人源化 CD19 CAR-T 细胞疗法可能是 mCD19 CAR-T 治疗后复发或耐药的 CD19 阳性 B-ALL 患者的治疗选择，CR 患者接受 hCD19 CAR-T 后进行 allo-HCT 可获得更长的缓解期。然而，对 hCD19 CAR-T 无反应者的预后仍然很差。
试验注册
中国临床试验注册中心/WHO 国际临床试验注册平台（ ChiCTR1900024456 ，网址：www.chictr.org.cn ）；注册于 2019 年 7 月 12 日。
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