Safety and feasibility of anti-CD19 CAR T cells expressing inducible IL-7 and CCL19 in patients with relapsed or refractory large B-cell lymphoma.
Safety and feasibility of anti-CD19 CAR T cells expressing inducible IL-7 and CCL19 in patients with relapsed or refractory large B-cell lymphoma.
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DOI：
10.1038/s41421-023-00625-0
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发表时间：
2024-01-09
期刊：
影响因子：
33.5
通讯作者：
Qian, Wenbin
中科院分区：
文献类型：
--
作者：
Lei, Wen;Zhao, Ai;Liu, Hui;Yang, Chunmei;Wei, Cheng;Guo, Shanshan;Chen, Zhilu;Guo, Qunyi;Li, Linjie;Zhao, Mingzhe;Wu, Gongqiang;Ouyang, Guifang;Liu, Ming;Zhang, Jinyi;Gao, Jimin;Qian, Wenbin
尽管 CD19 特异性嵌合抗原受体 (CAR) T 细胞可以治愈复发或难治性大 B 细胞淋巴瘤 (R/R LBCL) 患者，但肿瘤抗原阳性的疾病复发仍然是一个挑战。表达细胞因子/趋化因子的 CAR-T 细胞可以克服抑制环境，但这种 CAR-T 疗法的临床安全性和有效性仍不清楚。在这里，我们报告了能够在CD19接合后表达白介素（IL）-7和趋化因子（C-C基序）配体（CCL）-19的CD19特异性CAR-T细胞（称为7 × 19 CAR-T细胞）的临床前开发，以及7 × 19 CAR-T细胞治疗R/R LBCL患者的1期和扩展期试验的结果（NCT03258047）。在剂量递增阶段，没有观察到剂量限制性毒性。 39 名 R/R LBCL 患者接受了 7 × 19 CAR-T，剂量范围为每公斤体重 0.5 × 106–4.0 × 106 个细胞。 5 名患者（12.8%）发生 3 级细胞因子释放综合征，4 名患者（10.3%）发生 ≥ 3 级神经毒性。单次输注后 3 个月的总体缓解率为 79.5%（完全缓解，56.4%；部分缓解，23.1%）。中位随访时间为 32 个月，中位无进展生存期为 13 个月，中位总生存期尚未达到，两年时估计率为 53.8%（95% CI，40.3% 至 72.0%）。总之，来自多中心临床研究的长期随访数据表明，7 × 19 CAR-T 细胞可以诱导持久反应，中位总生存期超过 2 年，并且在 R/R LBCL 患者中具有可控的安全性。
Although CD19-specific chimeric antigen receptor (CAR) T cells are curative for patients with relapsed or refractory large B-cell lymphoma (R/R LBCL), disease relapse with tumor antigen-positive remains a challenge. Cytokine/chemokine-expressing CAR-T cells could overcome a suppressive milieu, but the clinical safety and efficacy of this CAR-T therapy remain unclear. Here we report the preclinical development of CD19-specific CAR-T cells capable of expressing interleukin (IL)-7 and chemokine (C-C motif) ligand (CCL)-19 upon CD19 engagement (referred to as 7 × 19 CAR-T cells) and results from a phase 1 and expansion phase trial of 7 × 19 CAR-T cell therapy in patients with R/R LBCL (NCT03258047). In dose-escalation phase, there were no dose-limiting toxicities observed. 39 patients with R/R LBCL received 7 × 19 CAR-T with doses ranged from 0.5 × 106–4.0 × 106 cells per kg body weight. Grade 3 cytokine release syndrome occurred in 5 (12.8%) patients and ≥ grade 3 neurotoxicity in 4 (10.3%) patients. The overall response rate at 3 months post-single infusion was 79.5% (complete remission, 56.4%; partial response, 23.1%). With a median follow-up of 32 months, the median progression-free survival was 13 months, and median overall survival was not reached, with an estimated rate of 53.8% (95% CI, 40.3% to 72.0%) at two years. Together, these long-term follow-up data from the multicenter clinical study suggest that 7 × 19 CAR-T cells can induce durable responses with a median overall survival of greater than 2 years, and have a manageable safety profile in patients with R/R LBCL.
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影响因子：
64.8
作者：
通讯作者：
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DOI：
10.1056/nejmoa1707447
发表时间：
2017-12-28
期刊：
The New England journal of medicine
影响因子：
--
作者：
Neelapu SS;Locke FL;Bartlett NL;Lekakis LJ;Miklos DB;Jacobson CA;Braunschweig I;Oluwole OO;Siddiqi T;Lin Y;Timmerman JM;Stiff PJ;Friedberg JW;Flinn IW;Goy A;Hill BT;Smith MR;Deol A;Farooq U;McSweeney P;Munoz J;Avivi I;Castro JE;Westin JR;Chavez JC;Ghobadi A;Komanduri KV;Levy R;Jacobsen ED;Witzig TE;Reagan P;Bot A;Rossi J;Navale L;Jiang Y;Aycock J;Elias M;Chang D;Wiezorek J;Go WY
通讯作者：
Go WY
影响因子：
82.9
作者：
Deng Q;Han G;Puebla-Osorio N;Ma MCJ;Strati P;Chasen B;Dai E;Dang M;Jain N;Yang H;Wang Y;Zhang S;Wang R;Chen R;Showell J;Ghosh S;Patchva S;Zhang Q;Sun R;Hagemeister F;Fayad L;Samaniego F;Lee HC;Nastoupil LJ;Fowler N;Eric Davis R;Westin J;Neelapu SS;Wang L;Green MR
通讯作者：
Green MR
DOI：
10.1038/s41571-023-00754-1
发表时间：
2023-06
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
通讯作者：
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影响因子：
20.3
作者：
Kochenderfer, James N.;Wilson, Wyndham H.;Rosenberg, Steven A.
通讯作者：
Rosenberg, Steven A.