同种异基因CAR-T细胞治疗复发/难治多发性骨髓瘤四例临床观察并文献复习  

Allogeneic CAR-T for treatment of relapsed and/or refractory multiple myeloma: four cases report and literatures review

作　　者：颜灵芝[1] 商京晶[1] 施晓兰[1] 瞿苏 康立清 徐南 常伟荣[1] 俞磊 吴德沛[1] 傅琤琤[1] Yan Lingzhi;Shang Jingjing;Shi Xiaolan;Qu Su;Kang Liqing;Xu Nan;Chang Weirong;Yu Lei;WuDepei;Fu Chengcheng(The First Affiliated Hospital of Soochow University,Jiangsu Institute of Hematology,CollaborativeInnovation Center of Hematology,Suzhou215006,China;Shanghai Unicar-Therapy Biomed-Phamaceutical Technology CO,LTD,Shanghai201203,China)

机构地区：[1]苏州大学附属第一医院血液科、江苏省血液研究所,血液学协同创新中心,215006 [2]上海优卡迪生物医药科技有限公司,201203

出　　处：《中华血液学杂志》2019年第8期650-655,共6页Chinese Journal of Hematology

基　　金：江苏省自然科学基金(BK20160342、BK20161205).

摘　　要：目的 探讨同种异基因CAR-T细胞治疗复发/难治型多发性骨髓瘤(RRMM)的安全性和有效性.方法 采集HLA不全相合健康供者外周血淋巴细胞制备CAR-T细胞治疗4例RRMM患者,男1例、女3例.细胞来源3例为亲缘间HLA半相合供者,1例为HLA完全不合的无血缘供者.4例RRMM患者经FC方案(氟达拉滨+环磷酰胺)预处理后进行CAR-T细胞的回输,第0天回输CART-19细胞1×107/kg、第1~2天分别回输CART-B细胞成熟抗原(BCMA)细胞4.7(4.0~6.8)×107/kg的40%和60%(例4于第4天回输CART-BCMA细胞的60%).结果 4例RRMM患者完成了CAR-T细胞输注后,CAR-T细胞在患者体内中位扩增2.20(1.93~14.01)倍,中位存活时间为10(8~36)d;根据IMWG疗效标准,2例达部分缓解(PR)、1例为微小缓解(MR)、1例为疾病稳定(SD).不良反应包括血液学和非血液学不良反应,≥3级血液学不良反应2例、≥3级细胞因子释放综合征(CRS)1例、1级CAR-T治疗后急性反应期的中枢神经系统并发症(CRES)1例,3例患者出现APTT延长、1例患者出现肿瘤溶解综合征,1例检测到STR为混合嵌合状态,临床判断出现GVHD.无进展生存时间为4(3~5)周、总生存时间为63(3~81)周.结论 小样本研究显示同种异基因CAR-T细胞治疗RRMM可能会出现GVHD;回输后早期有临床反应,但疗效不能维持.同种异基因CAR-T细胞在体内扩增倍数低,持续时间短,可能是影响疗效持久的主要因素.Objective To investigate the safety and efficacy of allogeneic CAR-T cells in the treatment of relapsed/refractory multiple myeloma(RRMM).Methods CAR-T cells were prepared from peripheral blood lymphocytes of HLA mismatch healthy donors.Median age was 55(48-60).Allogeneic cells were derived from 3 HLA haploidentical donors and 1 HLA completely mismatch unrelated donor.Four patients with RRMM were conditioned with FC regimen followed by CAR-T cell transfusion.They were infused into CART-19(1×107/kg on day 0)and(4.0-6.8)×107/kg CART-BCMA cells as split-dose infusions(40%on day 1 and 60%on day 2).The adverse reactions and clinical efficacy were observed during follow-up after infusion,and the amplification and duration of CAR-T cells in vivo were monitored by PCR technique.Results CAR-T cells were successfully infused in 3 of the 4 RRMM patients according to the study plan,and the infusion in one patient was delayed by 1 day due to high fever and elevated creatinine levels on day 3.The side effects included hematological and non-hematological toxicity,grade 3 hematological toxicity in 2 patients,grade 3 CRS in 1 one,grade 1 CRES in 1 one,prolonged APTT in 3 ones,tumor lysis syndrome in 1 one,mixed chimerism detected STR and clinical GVHD manifestation in 1 one.According to the efficacy criterias of IMWG,2 patients acquired PR,1 MR,and 1 SD respectively.Progression-free survival was 4(3-5)weeks and overall survival was 63(3-81)weeks.CAR T cells were amplified 2.2(2-14)times in the patients with a median survival time of 10(8-36)days.Conclusions Small sample studies suggested that GVHD may be present in the treatment of RRMM with allogeneic CAR-T cells.There were early clinical transient events after transfusion.Low amplification and short duration of CAR-T cells in vivo may be the main factors affecting the efficacy.

关 键 词：多发性骨髓瘤 复发/难治 嵌合型抗原受体T细胞疗法 

分 类 号：R73[医药卫生—肿瘤]