Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial
Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial
复制标题
DOI：
10.1038/s41591-020-1081-3
复制
发表时间：
2020-10-05
期刊：
影响因子：
82.9
通讯作者：
Hari, Parameswaran
中科院分区：
文献类型：
--
作者：
Shah, Nirav N.;Johnson, Bryon D.;Hari, Parameswaran
靶向CD 19的嵌合抗原受体（CAR）T细胞是复发性、难治性B细胞恶性肿瘤的突破性治疗（1-5）。尽管结果令人印象深刻，但CD 19（-）疾病的复发仍然是一个挑战。我们通过双特异性抗CD 20、抗CD 19（LV20.19）CAR T细胞治疗复发性、难治性B细胞恶性肿瘤的首次人体试验解决了这一局限性。B细胞非霍奇金淋巴瘤或慢性淋巴细胞白血病成人患者接受了1期剂量递增和扩展试验（NCT 03019055）治疗，以评价4- 1BB-CD 3 zeta LV 20. 19 CAR T细胞的安全性和使用CliniMACS Prodigy系统现场生产的可行性。CAR T细胞剂量范围为2.5 × 10（5）-2.5 × 10（6）个细胞/kg。细胞生产设定为14天，目标是输注未冷冻保存的LV20.19 CAR T细胞。所有未接受过CAR治疗的患者均达到了LV20.19 CAR T细胞的目标剂量，22例患者按方案接受了LV20.19 CAR T细胞。在不存在剂量限制性毒性的情况下，选择2.5 x 10（6）个细胞/kg的剂量进行扩增。1例（5%）患者发生3-4级细胞因子释放综合征，3例（14%）患者发生3-4级神经毒性。18例（82%）患者在第28天达到总体缓解，14例（64%）患者完全缓解，4例（18%）患者部分缓解。非冻存输注（n = 12）的2.5 x 10（6）个细胞/kg剂量的总体应答率为100%（完全应答，92%;部分应答，8%）。值得注意的是，在复发或经历治疗失败的患者中未观察到CD 19抗原的丢失。总之，现场制造和输注非冷冻保存的LV20.19 CAR T细胞是可行的，并且在治疗上是安全的，显示出低毒性和高功效。双特异性汽车可以通过减轻作为复发机制的靶抗原下调来改善临床应答。
Chimeric antigen receptor (CAR) T cells targeting CD19 are a breakthrough treatment for relapsed, refractory B cell malignancies(1-5). 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-CD3 zeta 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 x 10(5)-2.5 x 10(6) 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 x 10(6) 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 x 10(6) 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.