Davila Marco L, Riviere Isabelle, Wang Xiuyan, Bartido Shirley, Park Jae, Curran Kevin, Chung Stephen S, Stefanski Jolanta, Borquez-Ojeda Oriana, Olszewska Malgorzata, Qu Jinrong, Wasielewska Teresa, He Qing, Fink Mitsu, Shinglot Himaly, Youssif Maher, Satter Mark, Wang Yongzeng, Hosey James, Quintanilla Hilda, Halton Elizabeth, Bernal Yvette, Bouhassira Diana C G, Arcila Maria E, Gonen Mithat, Roboz Gail J, Maslak Peter, Douer Dan, Frattini Mark G, Giralt Sergio, Sadelain Michel, Brentjens Renier
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Sci Transl Med. 2014 Feb 19;6(224):224ra25. doi: 10.1126/scitranslmed.3008226.
We report on 16 patients with relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL) that we treated with autologous T cells expressing the 19-28z chimeric antigen receptor (CAR) specific to the CD19 antigen. The overall complete response rate was 88%, which allowed us to transition most of these patients to a standard-of-care allogeneic hematopoietic stem cell transplant (allo-SCT). This therapy was as effective in high-risk patients with Philadelphia chromosome-positive (Ph(+)) disease as in those with relapsed disease after previous allo-SCT. Through systematic analysis of clinical data and serum cytokine levels over the first 21 days after T cell infusion, we have defined diagnostic criteria for a severe cytokine release syndrome (sCRS), with the goal of better identifying the subset of patients who will likely require therapeutic intervention with corticosteroids or interleukin-6 receptor blockade to curb the sCRS. Additionally, we found that serum C-reactive protein, a readily available laboratory study, can serve as a reliable indicator for the severity of the CRS. Together, our data provide strong support for conducting a multicenter phase 2 study to further evaluate 19-28z CAR T cells in B-ALL and a road map for patient management at centers now contemplating the use of CAR T cell therapy.
我们报告了16例复发或难治性B细胞急性淋巴细胞白血病（B-ALL）患者，我们用表达针对CD19抗原的19-28z嵌合抗原受体（CAR）的自体T细胞对其进行治疗。总体完全缓解率为88%，这使我们能够将这些患者中的大多数过渡到标准治疗的异基因造血干细胞移植（allo-SCT）。这种疗法在费城染色体阳性（Ph(+)）疾病的高危患者中与在先前allo-SCT后复发疾病的患者中一样有效。通过对T细胞输注后前21天的临床数据和血清细胞因子水平进行系统分析，我们定义了严重细胞因子释放综合征（sCRS）的诊断标准,目标是更好地识别可能需要用皮质类固醇或白细胞介素-6受体阻断进行治疗干预以控制sCRS的患者亚组。此外，我们发现血清C反应蛋白，一项易于获得的实验室检查，可以作为CRS严重程度可靠指标。总之，我们的数据为开展一项多中心2期研究以进一步评估19-28z CAR T细胞在B-ALL中的作用以及为目前正在考虑使用CAR T细胞疗法的中心提供患者管理路线图提供了有力支持。
