Novel CD19 chimeric antigen receptor T cells manufactured next-day for acute lymphoblastic leukemia.
Novel CD19 chimeric antigen receptor T cells manufactured next-day for acute lymphoblastic leukemia.
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次日制造的新型 CD19 嵌合抗原受体 T 细胞用于治疗急性淋巴细胞白血病
DOI：
10.1038/s41408-022-00688-4
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发表时间：
2022-06-24
影响因子：
12.8
通讯作者：
Zhang, Xi
中科院分区：
文献类型：
--
作者：
Zhang, Cheng;He, Jiaping;Liu, Li;Wang, Jishi;Wang, Sanbin;Liu, Ligen;Ge, Jian;Gao, Lei;Gao, Li;Kong, Peiyan;Liu, Yao;Liu, Jia;Han, Yu;Zhang, Yongliang;Sun, Zhe;Ye, Xun;Yin, Wenjie;Sersch, Martina;Shen, Lianjun;Cao, Wei William;Zhang, Xi
嵌合抗原受体工程化T（CAR-T）细胞在复发性/难治性B细胞急性淋巴细胞白血病（R/R B-ALL）患者中显示出有希望的疗效。然而，挑战仍然存在，包括需要克服的长期制造过程。我们展示了第二天生产的靶向CD 19的CAR-T细胞产品GC 007 F（FasTCAR-T细胞），并给予R/R B-ALL患者。共筛选、入组了21例年龄超过14岁的CD 19 +R/R B-ALL患者，并以三种不同剂量水平单次输注GC 007 F CAR-T。本研究的主要目的是评估安全性，次要目的包括GC 007 F细胞在R/R B-ALL患者中的药代动力学和初步疗效。我们能够在临床前研究中证明，GC 007 F细胞比传统的CAR-T（C-CAR-T）细胞表现出更好的增殖和肿瘤杀伤。在这项由化疗药物启动的研究中，所有18例疗效可评价患者在第28天均达到完全缓解（CR）（18/18，100.00%），其中17例患者（94.4%）达到CR，微小残留病（MRD）阴性。15例患者（83.3%）在3个月评估时保持无疾病，14例患者（77.8%）在3个月时保持MRD阴性。在所有21例入组患者中，CAR-T细胞的中位峰值出现在第10天，中位峰值拷贝数为104899.5/µg DNA，中位持续时间为56天（范围：7-327天）。细胞因子释放综合征（CRS）的发生率为95.2%（n= 20），其中重度CRS发生率为52.4%（n= 11）。6例患者（28.6%）发生任何级别的神经毒性。与（C-CAR-T）细胞相比，GC 007 F表现出上级扩增能力和较少耗尽的表型。此外，这项首次人体临床研究表明，新型次日生产的FasTCAR-T细胞在R/R B-ALL患者中具有可管理的毒性特征。
Chimeric antigen receptor-engineered T (CAR-T) cells have shown promising efficacy in patients with relapsed/refractory B cell acute lymphoblastic leukemia (R/R B-ALL). However, challenges remain including long manufacturing processes that need to be overcome. We presented the CD19-targeting CAR-T cell product GC007F manufactured next-day (FasTCAR-T cells) and administered to patients with R/R B-ALL. A total of 21 patients over 14 years of age with CD19+R/R B-ALL were screened, enrolled and infused with a single infusion of GC007F CAR-T at three different dose levels. The primary objective of the study was to assess safety, secondary objectives included pharmacokinetics of GC007F cells in patients with R/R B-ALL and preliminary efficacy. We were able to demonstrate in preclinical studies that GC007F cells exhibited better proliferation and tumor killing than conventional CAR-T (C-CAR-T) cells. In this investigator-initiated study all 18 efficacy-evaluable patients achieved a complete remission (CR) (18/18, 100.00%) by day 28, with 17 of the patients (94.4%) achieving CR with minimal residual disease (MRD) negative. Fifteen (83.3%) remained disease free at the 3-month assessment, 14 patients (77.8%) maintaining MRD negative at month 3. Among all 21 enrolled patients, the median peak of CAR-T cell was on day 10, with a median peak copy number of 104899.5/µg DNA and a median persistence period of 56 days (range: 7–327 days). The incidence of cytokine release syndrome (CRS) was 95.2% (n= 20), with severe CRS occurring in 52.4% (n= 11) of the patients. Six patients (28.6%) developed neurotoxicity of any grade. GC007F demonstrated superior expansion capacity and a less exhausted phenotype as compared to (C-CAR-T) cells. Moreover, this first-in-human clinical study showed that the novel, next-day manufacturing FasTCAR-T cells was feasible with a manageable toxicity profile in patients with R/R B-ALL.
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影响因子：
15.9
作者：
Berger, Carolina;Jensen, Michael C.;Riddell, Stanley R.
通讯作者：
Riddell, Stanley R.
影响因子：
20.3
作者：
Gardner, Rebecca A.;Finney, Olivia;Jensen, Michael C.
通讯作者：
Jensen, Michael C.
DOI：
10.1038/nrc3322
发表时间：
2012-10
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Gattinoni L;Klebanoff CA;Restifo NP
通讯作者：
Restifo NP
影响因子：
82.9
作者：
Gattinoni L;Lugli E;Ji Y;Pos Z;Paulos CM;Quigley MF;Almeida JR;Gostick E;Yu Z;Carpenito C;Wang E;Douek DC;Price DA;June CH;Marincola FM;Roederer M;Restifo NP
通讯作者：
Restifo NP
影响因子：
20.3
作者：
Hinrichs, Christian S.;Borman, Zachary A.;Restifo, Nicholas P.
通讯作者：
Restifo, Nicholas P.