人源化与鼠源CD19 CAR-T细胞疗法治疗复发/难治急性B淋巴细胞白血病的长期随访  

Long-term follow-up of humanized and murine CD19 CAR-T-cell therapy for B-cell acute lymphoblastic leukemia

作　　者：都孟仪 张寅嫱 廖丹颖 谢薇 熊巍 梅恒 胡豫[1,2] Du Mengyi;Zhang Yinqiang;Liao Danying;Xie Wei;Xiong Wei;Mei Heng;Hu Yu(Institute of Hematology,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China;Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease,Wuhan 430022,China)

机构地区：[1]华中科技大学同济医学院附属协和医院血液科,武汉430022 [2]湖北省肿瘤疾病细胞治疗临床医学研究中心,武汉430022

出　　处：《中华血液学杂志》2023年第10期793-799,共7页Chinese Journal of Hematology

基　　金：国家自然科学基金(82070124);湖北省重点研发专项(2023BCB019)。

摘　　要：目的探索人源化和鼠源CD19嵌合抗原受体T细胞(CAR-T细胞)治疗复发/难治急性B淋巴细胞白血病(B-ALL)安全性、短期及长期随访的疗效差异。方法分析2016年5月至2023年3月于华中科技大学同济医学院附属协和医院接受CD19 CAR-T细胞治疗的80例R/R B-ALL患者的有效性和安全性,其中接受鼠源CAR-T治疗31例,人源化CAR-T治疗49例。结果鼠源和人源化组患者发生细胞因子释放综合征(CRS)的比例分别为61.3%和65.3%,其中接受鼠源CAR-T的患者发生重症CRS的比例高于人源化CAR-T(19.4%对8.2%,P=0.174),两组中分别有1例患者死于严重CRS。1~2级免疫效应细胞相关神经毒性综合征(ICANS)的发生率为12.9%和6.1%,无患者发生高级别ICANS。鼠源组和人源化组中白血病患者的总体反应率分别为74.2%和87.8%。在中位时间为10.5个月的随访期中,两组患者中位无复发生存(RFS)期均为12个月,中位总生存(OS)期均未达到。在45例基线骨髓白血病细胞负荷>20%的患者中,接受人源化CAR-T治疗的患者1年PFS率显著高于鼠源组(43.25%对33.33%,P=0.027)。桥接移植是改善B-ALL患者OS(χ^(2)=8.017,P=0.005)及RFS(χ^(2)=6.584,P=0.010)的独立影响因素。常见高危因素(年龄、骨髓高肿瘤负荷、BCR-ABL融合基因)对长期随访结果无显著影响。3例人源化组患者多次回输后仍达完全缓解,1例鼠源组患者复发后二次回输鼠源CAR-T细胞RFS期仅1个月。结论与接受鼠源CAR-T疗法治疗的患者相比,人源化CAR-T在不影响安全性的前提下,在高肿瘤负荷患者中显示出更持久的疗效,并有效克服免疫原性导致的CAR-T耐药,为多次复发患者提供治疗选择。Objective Murine CD19 chimeric antigen receptor T-cell(CAR-T)products have been approved for the treatment of refractory/relapsed(R/R)B-cell acute lymphocytic leukemia(B-ALL);moreover,humanized products are also undergoing clinical trials.This study aimed to explore the differences in safety and short-and long-term follow-up efficacy between humanized and murine CD19 CAR-T-cells for treating relapsed and refractory B-ALL.Methods Clinical data of 80 patients with R/R B-ALL treated with CD19-targeted CAR-T-cells at the Union Hospital of Tongji Medical College of Huazhong University of Science and Technology between May 2016 and March 2023 were analyzed,which included 31 patients with murine CAR-T and 49 with humanized products.Results The proportion of patients with cytokine-release syndrome(CRS)in the murine and humanized groups was 63.1%and 65.3%,respectively.Moreover,a higher proportion of patients suffered from severe CRS in the murine group than in the humanized CAR-T group(19.4%vs 8.2%,P=0.174).Furthermore,one patient per group died of grade 5 CRS.The incidence of grade 1–2 immune effector cell-associated neurotoxicity syndrome(ICANS)was 12.9%and 6.1%,respectively;severe ICANS were not observed.Among patients receiving murine CAR-T-cells,an overall response(OR)was observed in 74.2%.Conversely,the OR rate of patients receiving humanized CAR-T-cells was 87.8%.During the median follow-up time of 10.5 months,the median recurrence-free survival(RFS)of patients with murine CAR-T-cells was 12 months,which was as long as that of patients with humanized CAR-T-cells.The median overall survival(OS)were not reached in both groups.Of the 45 patients with a bone marrow burden over 20%at baseline,humanized CAR-T therapy was associated with a significantly improved RFS(43.25%vs 33.33%,P=0.027).Bridging transplantation was an independent factor in prolonging OS(χ^(2)=8.017,P=0.005)and PFS(χ^(2)=6.584,P=0.010).Common risk factors,such as age,high proportion of bone marrow blasts,and BCR-ABL fusion gene expression,had no si

关 键 词：嵌合抗原受体T细胞 人源化 急性B淋巴细胞白血病 长期随访 

分 类 号：R733.7[医药卫生—肿瘤]