细胞因子释放综合征
CD19
CD20
淋巴瘤
耐火材料(行星科学)
嵌合抗原受体
慢性淋巴细胞白血病
B细胞
医学
T细胞
白血病
内科学
胃肠病学
肿瘤科
抗体
免疫学
抗原
免疫系统
生物
天体生物学
作者
Nirav N. Shah,Bryon D. Johnson,Dina Schneider,Fenlu Zhu,Anikó Szabó,Carolyn A. Keever-Taylor,Winfried Krueger,Andrew Worden,Michael J. Kadan,Sharon Yim,Ashley M. Cunningham,Mehdi Hamadani,Timothy S. Fenske,Boro Dropulić,Rimas J. Orentas,Parameswaran Hari
出处
期刊:Nature Medicine
[Springer Nature]
日期:2020-10-01
卷期号:26 (10): 1569-1575
被引量:282
标识
DOI:10.1038/s41591-020-1081-3
摘要
Chimeric antigen receptor (CAR) T cells targeting CD19 are a breakthrough treatment for relapsed, refractory B cell malignancies1–5. Despite impressive outcomes, relapse with CD19− disease remains a challenge. We address this limitation through a first-in-human trial of bispecific anti-CD20, anti-CD19 (LV20.19) CAR T cells for relapsed, refractory B cell malignancies. Adult patients with B cell non-Hodgkin lymphoma or chronic lymphocytic leukemia were treated on a phase 1 dose escalation and expansion trial (NCT03019055) to evaluate the safety of 4-1BB–CD3ζ LV20.19 CAR T cells and the feasibility of on-site manufacturing using the CliniMACS Prodigy system. CAR T cell doses ranged from 2.5 × 105–2.5 × 106 cells per kg. Cell manufacturing was set at 14 d with the goal of infusing non-cryopreserved LV20.19 CAR T cells. The target dose of LV20.19 CAR T cells was met in all CAR-naive patients, and 22 patients received LV20.19 CAR T cells on protocol. In the absence of dose-limiting toxicity, a dose of 2.5 × 106 cells per kg was chosen for expansion. Grade 3–4 cytokine release syndrome occurred in one (5%) patient, and grade 3–4 neurotoxicity occurred in three (14%) patients. Eighteen (82%) patients achieved an overall response at day 28, 14 (64%) had a complete response, and 4 (18%) had a partial response. The overall response rate to the dose of 2.5 × 106 cells per kg with non-cryopreserved infusion (n = 12) was 100% (complete response, 92%; partial response, 8%). Notably, loss of the CD19 antigen was not seen in patients who relapsed or experienced treatment failure. In conclusion, on-site manufacturing and infusion of non-cryopreserved LV20.19 CAR T cells were feasible and therapeutically safe, showing low toxicity and high efficacy. Bispecific CARs may improve clinical responses by mitigating target antigen downregulation as a mechanism of relapse. A new bispecific CAR T cell product targeting the CD20 and CD19 antigens demonstrates an excellent safety profile and high clinical efficacy in patients with B cell non-Hodgkin lymphoma and chronic lymphocytic leukemia.
科研通智能强力驱动
Strongly Powered by AbleSci AI