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双特异性CD20、CD19 CAR T细胞可用于复发性B细胞恶性肿瘤治疗
2020-10-11 21:21
来源：小柯机器人

美国Lentigen公司Boro Dropuli、威斯康辛医学院Nirav N. Shah等研究人员发现，双特异性CD20、CD19 CAR T细胞可用于复发性B细胞恶性肿瘤治疗。 相关论文于2020年10月5日发表于国际学术期刊《自然—医学》。

据研究人员介绍，靶向CD19的嵌合抗原受体（CAR）T细胞是复发难治性B细胞恶性肿瘤的突破性疗法。尽管结果令人印象深刻，但CD19疾病的复发仍然是一个挑战。
 
通过使用双特异性抗CD20、抗CD19（LV20.19）CAR T细胞来治疗复发难治性B细胞恶性肿瘤的首次人类试验，研究人员解决了这一局限性。对成人B细胞非霍奇金淋巴瘤或慢性淋巴细胞性白血病患者进行了1期剂量递增和扩增试验（NCT03019055），用以评估4-1BB–CD3ζ LV20.19 CAR T细胞的安全性以及现场制造的可行性（使用CliniMACS Prodigy系统来评估）。 CAR T细胞剂量范围为每公斤2.5×105至2.5×106个细胞。
 
为注入非冷冻保存的LV20.19 CAR T细胞，细胞制造时间被设定为14天。在所有未接受过CAR的患者中均达到了LV20.19 CAR T细胞的目标剂量，并且有22例患者在治疗方案中接受了LV20.19 CAR T细胞。在没有剂量限制性毒性的情况下，选择每公斤2.5×106个细胞进行扩增。一名（5％）患者发生3-4级细胞因子释放综合征，三名（14％）患者发生3-4级神经毒性。18例（82％）患者在第28天获得了总体缓解，其中14例（64％）完全缓解，4例（18％）部分缓解。非冷冻保存的输注对每公斤2.5×106个细胞剂量的总缓解率为100％（完全缓解率为92％；部分缓解率为8％）（n = 12）。
 
值得注意的是，在复发或经历治疗失败的患者中未观察到CD19抗原的丢失。总之，非冷冻保存的LV20.19 CAR T细胞的现场制造和输注是可行且治疗安全的，且显示出低毒性和高疗效。双特异性CAR可以通过减轻靶抗原下调作为复发机制来改善临床反应。
 
附：英文原文

Title: Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial

Author: Nirav N. Shah, Bryon D. Johnson, Dina Schneider, Fenlu Zhu, Aniko Szabo, Carolyn A. Keever-Taylor, Winfried Krueger, Andrew A. Worden, Michael J. Kadan, Sharon Yim, Ashley Cunningham, Mehdi Hamadani, Timothy S. Fenske, Boro Dropuli, Rimas Orentas, Parameswaran Hari

Issue&Volume: 2020-10-05

Abstract: Chimeric antigen receptor (CAR) T cells targeting CD19 are a breakthrough treatment for relapsed, refractory B cell malignancies1,2,3,4,5. 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 14d 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.

DOI: 10.1038/s41591-020-1081-3

Source: https://www.nature.com/articles/s41591-020-1081-3

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
官方网址：https://www.nature.com/nm/
投稿链接：https://mts-nmed.nature.com/cgi-bin/main.plex


本期文章：《自然—医学》：Online/在线发表

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