Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults
Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults
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DOI：
10.1182/blood-2017-02-769208
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发表时间：
2017-06-22
期刊：
影响因子：
20.3
通讯作者：
Jensen, Michael C.
中科院分区：
文献类型：
--
作者：
Gardner, Rebecca A.;Finney, Olivia;Jensen, Michael C.
将cd19导向的嵌合抗原受体（CAR） T细胞从复发患者的早期试验过渡到一种可行的治疗方法，具有可预测的疗效和低毒性，可广泛应用于高未满足需求的患者，目前由于未定义T细胞混合物的转导、转基因表达的可变性和细胞在培养结束时的终末分化而导致的产品异质性，使其变得复杂。一项针对45名复发或难治性b系急性淋巴细胞白血病的儿童和年轻人的i期临床试验使用CD19 CAR产品进行，该产品具有明确的CD4/CD8组成、均匀的CAR表达和有限的效应分化。93%的入组患者使用了符合所有规定规格的产品。最大耐受剂量为每公斤106个CAR - T细胞，没有因产品毒性导致的死亡或脑水肿。该1期研究的总体意向治疗最小残留病阴性（MRD 2）缓解率为89%。在接受CAR - t细胞产品的患者中，MRD 2缓解率为93%，而在接受氟达拉滨和环磷酰胺淋巴细胞清除的患者亚群中，MRD 2缓解率为100%。23%的患者出现可逆性严重细胞因子释放综合征和/或可逆性严重神经毒性。这些数据表明，在一组预后不良的患者中，制造一种定义成分的CD19 CART细胞确定了一种具有高效抗肿瘤活性和可容忍的不良反应的最佳细胞剂量。
Transitioning CD19-directed chimeric antigen receptor (CAR) T cells from early-phase trials in relapsed patients to a viable therapeutic approach with predictable efficacy and low toxicity for broad application among patients with high unmet need is currently complicated by product heterogeneity resulting from transduction of undefined T-cell mixtures, variability of transgene expression, and terminal differentiation of cells at the end of culture. A phase 1 trial of 45 children and young adults with relapsed or refractory B-lineage acute lymphoblastic leukemia was conducted using a CD19 CAR product of defined CD4/CD8 composition, uniform CAR expression, and limited effector differentiation. Products meeting all defined specifications occurred in 93% of enrolled patients. The maximum tolerated dose was 10 6 CAR T cells per kg, and there were no deaths or instances of cerebral edema attributable to product toxicity. The overall intent-to-treat minimal residual disease-negative(MRD 2) remission rate for this phase 1 study was 89%. The MRD 2 remission rate was 93% in patients who received a CAR T-cell product and 100% in the subset of patients who received fludarabine and cyclophosphamide lymphodepletion. Twenty-three percent of patients developed reversible severe cytokine release syndrome and/or reversible severe neurotoxicity. These data demonstrate that manufacturing a defined-composition CD19 CART cell identifies an optimal cell dose with highly potent antitumor activity and a tolerable adverse effect profile in a cohort of patients with an otherwise poor prognosis.