造血干细胞移植后复发急性B淋巴细胞白血病CD19 CAR-T细胞治疗后的维持治疗  

Maintenance therapy following CD19 CAR-T treatment for relapsed B-cell acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation

作　　者：蒋怡丽 李青[1] 蒲业迪[1] 江嫣雨 袁婷 邓琦[1] 李玉明[1] 韩明哲 翟卫华 Jiang Yili;Li Qing;Pu Yedi;Jiang Yanyu;Yuan Ting;Deng Qi;Li Yuming;Han Mingzhe;Zhai Weihua(Department of Hematology,Tianjin First Central Hospital,Tianjin 300192,China;Institute of Hematology and Blood Diseases Hospital,CAMS&PUMC,National Clinical Research Center for Blood Diseases,Tianjin 300020,China)

机构地区：[1]天津市第一中心医院血液科,300192 [2]中国医学科学院血液病医院(中国医学科学院血液学研究所),国家血液系统疾病临床医学研究中心,天津300020

出　　处：《中华血液学杂志》2020年第6期495-501,共7页Chinese Journal of Hematology

摘　　要：目的探讨异基因造血干细胞移植后复发急性B淋巴细胞白血病(B-ALL)CD19 CAR-T细胞治疗缓解后的维持治疗,观察单独输注供者造血干细胞和供者T淋巴细胞对CD19 CAR-T细胞扩增的影响。方法 1例难治B-ALL患者,CD19 CAR-T(鼠源,克隆号:FMC63)细胞治疗后桥接同胞全相合异基因造血干细胞移植,后再次复发。接受CD19 CAR-T(可变区人源化的FMC63)细胞治疗再次缓解,缓解后先后接受单独输注供者造血干细胞、供者T淋巴细胞的维持治疗,期间监测患者细胞因子水平、CD19 CAR-T细胞比例、CD19 CAR的DNA表达变化,观察骨髓白血病细胞比例及供者嵌合情况。另外,通过制备小鼠CD19 CAR-T(FMC63)细胞,并将CAR-T细胞注射至同窝小鼠体内,14 d后,再次注射同窝小鼠的B淋巴细胞,在此过程中观察CAR-T细胞、B淋巴细胞比例以及CD19 CAR的DNA表达,以此来模拟临床治疗过程。结果①患者输注人源化CD19 CAR-T细胞后第14天,疗效评估达完全缓解(CR),供者嵌合率为99.76%,细胞因子释放综合征1级。②人源化CD19 CAR-T细胞治疗缓解后,单独输注供者造血干细胞维持治疗,输注后第24天出现移植物抗宿主病(GVHD),患者GVHD期间伴有外周血CD19 CAR-T细胞比例及CD19 CAR DNA水平的升高,并随GVHD缓解下降。过程中患者维持CR且供者嵌合率为99.69%。③随后单独输注供者T淋巴细胞维持治疗,回输后第12天患者出现GVHD,而患者外周血CD19 CAR-T细胞比例及CD19 CAR的DNA水平并未出现再次升高。过程中患者维持CR且供者嵌合率为99.87%。④C57小鼠体内试验证实,CAR-T细胞输注后小鼠体内CAR-T细胞扩增及DNA表达上调,同时CD19+ B淋巴细胞耗竭。之后输注CD19+ B淋巴细胞,CD19 CAR-T细胞扩增和CD19 CAR的DNA表达再度上调。结论供者造血干细胞、供者T淋巴细胞的单独输注,可作为异基因造血干细胞移植后复发B-ALL接受CD19 CAR-T治疗缓解后的维持治疗手段,且输注供者造血�Objective This study aimed to evaluate the maintenance therapy following an anti-CD19-CAR T-cell therapy for a B-cell acute lymphoblastic leukemia(ALL)patient who relapsed after allogeneic hematopoietic cell transplantation(allo-HSCT)and investigate the effect of donor stem cells and donor T lymphocyte infusion on the amplification of CD19 CAR-T cells.Methods One refractory B-ALL patient relapsed after murine CD19 CAR-T cell therapy followed by a sibling allo-HSCT.He underwent a humanized CD19 CAR-T cell therapy followed by donor stem cell and donor T lymphocytes infusions as maintenance therapy in our hospital.The level of cytokines,the proportion of CD19 CAR-T cell,the level of CAR19 DNA expression in the peripheral blood,and the proportion of leukemia cells and donor chimerism in the bone marrow were detected.Correspondingly,T lymphocytes from the C57 spleen were separated to modify the CD19 CAR lentivirus and refused into C57 mice,and after 14 days,the B lymphocytes from C57 mice were separated and refused into the same C57 mice.The CD19 CAR T cells,B cells,and CD19 CAR gene counts in the peripheral blood were evaluated at different time points.Results①The patient achieved a complete response(CR)14 days after a humanized CD19 CAR-T therapy with grade 1 cytokine release syndrome(CRS)and restored a donor chimerism to 99.76%.②Following the remission from humanized CD19 CAR-T therapy,the patient received a maintenance therapy of donor stem cell infusion.Mild graft-versus-host disease(GVHD)manifested 24 days after infusion with an increased proportion of CD19 CAR-T cells and an increased level of CAR19 DNA expression in the peripheral blood.It fell with the remission of GVHD.The patient maintained CR and 99.69%donor chimerism during this period.③Throughout the subsequent donor T lymphocytes maintenance therapy,mild GVHD surfaced12 days after infusion without an increased proportion of CD19 CAR-T cells and an increased level of CAR19 DNA expression in the peripheral blood.The patient maintained CR and 99.87%d

关 键 词：白血病 淋巴细胞 急性 复发 CAR-T细胞 供者造血干细胞 供者T淋巴细胞 造血干细胞移植 

分 类 号：R733.71[医药卫生—肿瘤]