Ceppi Francesco, Wilson Ashley L, Annesley Colleen, Kimmerly Gabriella R, Summers Corinne, Brand Adam, Seidel Kristy, Wu Qian Vicky, Beebe Adam, Brown Christopher, Mgebroff Stephanie, Lindgren Catherine, Rawlings-Rhea Stephanie D, Huang Wenjun, Pulsipher Michael A, Wayne Alan S, Park Julie R, Jensen Michael C, Gardner Rebecca A
Research Division, Seattle Children's Hospital, Seattle, Washington.
Pediatric Hematology-Oncology Unit, Division of Pediatrics, University Hospital of Lausanne, Lausanne, Switzerland.
Cancer Immunol Res. 2022 Jul 1;10(7):856-870. doi: 10.1158/2326-6066.CIR-21-0501.
T cells modified to express a chimeric antigen receptor (CAR) targeting CD19 can induce potent and sustained responses in children with relapsed/refractory acute lymphoblastic leukemia (ALL). The durability of remission is related to the length of time the CAR T cells persist. Efforts to understand differences in persistence have focused on the CAR construct, in particular the costimulatory signaling module of the chimeric receptor. We previously reported a robust intent-to-treat product manufacturing success rate and remission induction rate in children and young adults with recurrent/refractory B-ALL using the SCRI-CAR19v1 product, a second-generation CD19-specific CAR with 4-1BB costimulation coexpressed with the EGFRt cell-surface tag (NCT02028455). Following completion of the phase I study, two changes to CAR T-cell manufacturing were introduced: switching the T-cell activation reagent and omitting midculture EGFRt immunomagnetic selection. We tested the modified manufacturing process and resulting product, designated SCRI-CAR19v2, in a cohort of 21 subjects on the phase II arm of the trial. Here, we describe the unanticipated enhancement in product performance resulting in prolonged persistence and B-cell aplasia and improved leukemia-free survival with SCRI-CAR19v2 as compared with SCRI-CAR19v1.
经过改造以表达靶向CD19的嵌合抗原受体（CAR）的T细胞，可在复发/难治性急性淋巴细胞白血病（ALL）患儿中诱导出强烈且持久的反应。缓解的持久性与CAR T细胞持续存在的时间长短有关。为了解持续性差异所做的努力主要集中在CAR构建体上，特别是嵌合受体的共刺激信号模块。我们之前报道过，使用SCRI-CAR19v1产品（一种第二代CD19特异性CAR，与EGFRt细胞表面标签共表达4-1BB共刺激）治疗复发/难治性B-ALL儿童和年轻成人时，意向性治疗产品制造成功率和缓解诱导率都很高（NCT02028455）。在I期研究完成后，对CAR T细胞制造进行了两项改变：更换T细胞激活试剂并省略培养中期EGFRt免疫磁珠分选。我们在该试验II期队列的21名受试者中测试了改良后的制造工艺及所得产品，即SCRI-CAR19v2。在此，我们描述了与SCRI-CAR19v1相比，SCRI-CAR19v2在产品性能上出现的意外提升，表现为CAR T细胞持续时间延长、B细胞发育不全，以及无白血病生存率提高。
