氟达拉滨
医学
细胞因子释放综合征
环磷酰胺
内科学
不利影响
微小残留病
CD8型
肿瘤科
白血病
免疫学
嵌合抗原受体
T细胞
抗原
化疗
免疫系统
作者
Rebecca Gardner,Olivia Finney,Colleen Annesley,Hannah Brakke,Corinne Summers,Kasey J. Leger,Marie Bleakley,Christopher Brown,Stephanie Mgebroff,Karen S. Kelly-Spratt,Virginia Hoglund,Catherine Lindgren,Assaf P. Oron,Daniel Li,Stanley R. Riddell,Julie R. Park,Michael C. Jensen
出处
期刊:Blood
[American Society of Hematology]
日期:2017-06-22
卷期号:129 (25): 3322-3331
被引量:819
标识
DOI:10.1182/blood-2017-02-769208
摘要
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 106 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-) remission rate for this phase 1 study was 89%. The MRD- 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 CAR T 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. This trial was registered at www.clinicaltrials.gov as #NCT02028455.
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