期刊
BLOOD
卷 129, 期 25, 页码 3322-3331出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2017-02-769208
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资金
- Stand Up to Cancer
- St. Baldrick's Pediatric Dream Team Translational Research Grant [SU2C-AACR-DT1113]
- National Institutes of Health, National Cancer Institute [RO1 CA136551-05]
- Alex's Lemonade Stand Phase I/II Infrastructure Grant
- Conquer Cancer Foundation Career Development Award
- Washington State Life Sciences Discovery Fund
- Ben Towne Foundation
- William Lawrence and Blanche Hughes Foundation
- Juno Therapeutics, Inc.
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.
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