Factors associated with outcomes after a second CD19-targeted CAR T-cell infusion for refractory B-cell malignancies
Factors associated with outcomes after a second CD19-targeted CAR T-cell infusion for refractory B-cell malignancies
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DOI：
10.1182/blood.2020006770
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发表时间：
2021-01-21
期刊：
影响因子：
20.3
通讯作者：
Turtle, Cameron J.
中科院分区：
文献类型：
--
作者：
Gauthier, Jordan;Bezerra, Evandro D.;Turtle, Cameron J.
CD 19靶向嵌合抗原受体工程化（CD 19 CAR）T细胞疗法已显示出对复发性或难治性（R/R）B细胞恶性肿瘤的显著疗效。然而，CD 19 CAR T细胞在大多数患者中未能诱导持久的应答。第二次输注CD 19 CAR T细胞（CART 2）被认为是改善结局的可能方法。我们分析了44例R/R B细胞恶性肿瘤患者的数据（急性淋巴细胞白血病[ALL]，n = 14;慢性淋巴细胞白血病[CLL]，n = 9;非霍奇金淋巴瘤[NHL]，n = 21），这些患者在我们机构的1/2期试验（NCT 01865617）中接受了CART 2。尽管在82%的患者中CART 2剂量增加，但我们观察到CART 2后严重毒性的发生率较低（等级>= 3细胞因子释放综合征，9%;等级>= 3神经毒性，11%）。CART 2后，22%的CLL、19%的NHL和21%的ALL患者实现了完全缓解（CR）。在CLL、NHL和ALL患者中，CART 2后的中位缓解持续时间分别为33、6和4个月。在第一次CAR T细胞输注（CART 1）之前，将氟达拉滨添加到基于环磷酰胺的淋巴细胞清除中，以及与CART 1相比CART 2剂量的增加与CART 2后更高的总缓解率和更长的无进展生存期独立相关。我们在CART 1前接受环磷酰胺和氟达拉滨（Cy-Flu）淋巴细胞清除的患者中观察到CART 2后持久的CAR T细胞持久性，并且与CART 1细胞剂量相比，CART 2更高。鉴定出与CART 2后更好结果独立相关的2种可改变的预处理因素，表明了在重复CAR T细胞输注后改善体内CAR T细胞动力学和应答的策略，并对在先前CAR T细胞免疫疗法失败后设计新型CAR T细胞产品的试验具有意义。
CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T-cell therapy has shown significant efficacy for relapsed or refractory (R/R) B-cell malignancies. Yet, CD19 CAR T cells fail to induce durable responses in most patients. Second infusions of CD19 CAR T cells (CART2) have been considered as a possible approach to improve outcomes. We analyzed data from 44 patients with R/R B-cell malignancies (acute lymphoblastic leukemia [ALL], n = 14; chronic lymphocytic leukemia [CLL], n = 9; non-Hodgkin lymphoma [NHL], n = 21) who received CART2 on a phase 1/2 trial (NCT01865617) at our institution. Despite a CART2 dose increase in 82% of patients, we observed a low incidence of severe toxicity after CART2 (grade >= 3 cytokine release syndrome, 9%; grade >= 3 neurotoxicity, 11%). After CART2, complete response (CR) was achieved in 22% of CLL, 19% of NHL, and 21% of ALL patients. The median durations of response after CART2 in CLL, NHL, and ALL patients were 33, 6, and 4 months, respectively. Addition of fludarabine to cyclophosphamide-based lymphodepletion before the first CAR T-cell infusion (CART1) and an increase in the CART2 dose compared with CART1 were independently associated with higher overall response rates and longer progression-free survival after CART2. We observed durable CAR T-cell persistence after CART2 in patients who received cyclophosphamide and fludarabine (Cy-Flu) lymphodepletion before CART1 and a higher CART2 compared with CART1 cell dose. The identification of 2 modifiable pretreatment factors independently associated with better outcomes after CART2 suggests strategies to improve in vivo CAR T-cell kinetics and responses after repeat CAR T-cell infusions, and has implications for the design of trials of novel CAR T cell products after failure of prior CAR T cell immunotherapies.