Safety and tolerability of conditioning chemotherapy followed by CD19-targeted CAR T cells for relapsed/refractory CLL
Safety and tolerability of conditioning chemotherapy followed by CD19-targeted CAR T cells for relapsed/refractory CLL
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DOI：
10.1172/jci.insight.122627
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发表时间：
2019-05-02
期刊：
影响因子：
8
通讯作者：
Brentjens, Renier J.
中科院分区：
文献类型：
--
作者：
Geyer, Mark B.;Riviere, Isabelle;Brentjens, Renier J.
背景复发性或难治性（R/R）慢性淋巴细胞白血病（CLL）患者亚组在标准治疗（包括口服激酶抑制剂）后表现出次优结局。我们和其他人之前已经报道了自体CD 19靶向CART细胞对这些患者的安全性和有效性。在此，我们报告了CART细胞治疗伴或不伴预处理化疗的RJR CLL和惰性B细胞非霍奇金淋巴瘤（B-NHL）患者的安全性和长期随访。我们进行了一项I期临床试验，研究了结合CD 28共刺激结构域的CD 19靶向CART细胞（19- 28 z）。20例患者中有17例在CART细胞输注前接受了预处理化疗。5例CLL患者在自体T细胞采集和/或CART细胞给药时接受了伊鲁替尼。该分析包括16例RJR CLL患者和4例RJR惰性B-NHL患者。在所有20例患者中观察到细胞因子释放综合征（CRS），但3级和4级CRS和神经系统事件不常见（各10%）。在白细胞分离术时，接受伊鲁替尼治疗的患者中，T细胞的离体扩增和具有CD 62 L（+）CD 127（+）免疫表型的CART细胞比例显著更高（P = 0.047; CD 8亚群，P = 0.0061，am亚群）。接受预处理化疗的12例可评价CLL患者中有3例达到完全缓解（CR）（2例有最小残留疾病阴性CR）。所有达到CR的患者在中位随访53个月时仍保持无进展。在接受过大量预治疗的RJR CLL和惰性B-NHL患者中，在研究的剂量水平下，预处理化疗和19- 28 z CAR T细胞的耐受性可接受，并且一个亚组的患者实现了持久的CR。伊布替尼治疗可以调节自体T细胞表型。
BACKGROUND. Subgroups of patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) exhibit suboptimal outcomes after standard therapies, including oral kinase inhibitors. We and others have previously reported on the safety and efficacy of autologous CD19-targeted CART cells for these patients. Here, we report safety and long-term follow-up of CART cell therapy with or without conditioning chemotherapy for patients with RJR CLL and indolent B cell non-Hodgkin lymphoma (B-NHL).METHODS. We conducted a phase I clinical trial investigating CD19-targeted CART cells incorporating a CD28 costimulatory domain (19-28z). Seventeen of twenty patients received conditioning chemotherapy prior to CART cell infusion. Five patients with CLL received ibrutinib at the time of autologous T cell collection and/or CART cell administration.RESULTS. This analysis included 16 patients with RJR CLL and 4 patients with RJR indolent B-NHL. Cytokine release syndrome (CRS) was observed in all 20 patients, but grade 3 and 4 CRS and neurological events were uncommon (10% for each). Ex vivo expansion of T cells and proportions of CART cells with the CD62L(+)CD127(+) immunophenotype were significantly greater (P = 0.047; CD8 subset, P = 0.0061, am subset) in patients on ibrutinib at leukapheresis. Three of twelve evaluable CLL patients receiving conditioning chemotherapy achieved complete response (CR) (2 had minimal residual disease-negative CR). All patients achieving CR remained progression free at median follow-up of 53 months.CONCLUSION. Conditioning chemotherapy and 19-28z CAR T cells were acceptably tolerated across investigated dose levels in heavily pretreated patients with RJR CLL and indolent B-NHL, and a subgroup of patients achieved durable CR. lbrutinib therapy may modulate autologous T cell phenotype.