Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas.
Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas.
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DOI：
10.1056/nejmoa1708566
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发表时间：
2017-12-28
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影响因子：
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通讯作者：
June CH
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作者：
Schuster SJ;Svoboda J;Chong EA;Nasta SD;Mato AR;Anak Ö;Brogdon JL;Pruteanu-Malinici I;Bhoj V;Landsburg D;Wasik M;Levine BL;Lacey SF;Melenhorst JJ;Porter DL;June CH
免疫化疗和移植后复发的弥漫性大B细胞淋巴瘤或滤泡性淋巴瘤患者预后较差。针对CD19的嵌合抗原受体(CAR)修饰的T细胞在B细胞癌中的高应答率已被报道，尽管关于B细胞淋巴瘤的数据有限。我们使用了表达CD19导向CAR(CTL019)的自体T细胞来治疗已经复发或对以前的治疗无效的弥漫性大B细胞淋巴瘤或滤泡性淋巴瘤患者。监测患者对治疗的反应、毒性反应、CTL019细胞在体内的扩张和持久性以及免疫恢复。共28例成人淋巴瘤患者接受了CTL019细胞移植，其中18例有反应(%；95%可信区间[CI]，44至81)。14例弥漫性大B细胞淋巴瘤中6例完全缓解(43%，95%CI，18~71)，滤泡性淋巴瘤10例(71%，95%CI，42~92)。CTL019细胞在体内增殖，在有应答和无应答的患者的血液和骨髓中都能检测到。在中位数28.6个月的随访中，86%的弥漫性大B细胞淋巴瘤患者有效(95%CI，33~98)和89%的滤泡性淋巴瘤患者(95%CI，43~98)维持了有效。严重细胞因子释放综合征5例(18%)。发生严重脑病3例(11%)，自限2例，死亡1例。所有6个月完全缓解的患者在诱导后7.7~37.9个月(中位数29.3个月)仍处于缓解状态，16例患者中有8例B细胞持续出现，10例患者中4例在6个月或以上时免疫球蛋白G、6/10例在6个月或以后有改善，3/10例患者在18个月或以上时在免疫球蛋白A水平上有改善。CTL019细胞可有效治疗复发或难治性弥漫性大B细胞淋巴瘤和滤泡性淋巴瘤。观察到较高的持久缓解率，一些患者B细胞和免疫球蛋白恢复。大约三分之一的患者发展为一过性脑病，五分之一的患者发展为严重的细胞因子释放综合征。(由诺华等公司资助；ClinicalTrials.gov编号，NCT02030834。)
Patients with diffuse large B-cell lymphoma or follicular lymphoma that is refractory to or that relapses after immunochemotherapy and transplantation have a poor prognosis. High response rates have been reported with the use of T cells modified by chimeric antigen receptor (CAR) that target CD19 in B-cell cancers, although data regarding B-cell lymphomas are limited. We used autologous T cells that express a CD19-directed CAR (CTL019) to treat patients with diffuse large B-cell lymphoma or follicular lymphoma that had relapsed or was refractory to previous treatments. Patients were monitored for response to treatment, toxic effects, the expansion and persistence of CTL019 cells in vivo, and immune recovery. A total of 28 adult patients with lymphoma received CTL019 cells, and 18 of 28 had a response (64%; 95% confidence interval [CI], 44 to 81). Complete remission occurred in 6 of 14 patients with diffuse large B-cell lymphoma (43%; 95% CI, 18 to 71) and 10 of 14 patients with follicular lymphoma (71%; 95% CI, 42 to 92). CTL019 cells proliferated in vivo and were detectable in the blood and bone marrow of patients who had a response and patients who did not have a response. Sustained remissions were achieved, and at a median follow-up of 28.6 months, 86% of patients with diffuse large B-cell lymphoma who had a response (95% CI, 33 to 98) and 89% of patients with follicular lymphoma who had a response (95% CI, 43 to 98) had maintained the response. Severe cytokine-release syndrome occurred in 5 patients (18%). Serious encephalopathy occurred in 3 patients (11%); 2 cases were self-limiting and 1 case was fatal. All patients in complete remission by 6 months remained in remission at 7.7 to 37.9 months (median, 29.3 months) after induction, with a sustained reappearance of B cells in 8 of 16 patients and with improvement in levels of IgG in 4 of 10 patients and of IgM in 6 of 10 patients at 6 months or later and in levels of IgA in 3 of 10 patients at 18 months or later. CTL019 cells can be effective in the treatment of relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma. High rates of durable remission were observed, with recovery of B cells and immunoglobulins in some patients. Transient encephalopathy developed in approximately one in three patients and severe cytokine-release syndrome developed in one in five patients. (Funded by Novartis and others; ClinicalTrials.gov number, NCT02030834.)