背景:T细胞受体(TCR)-T细胞具有相似的效应子功能,但与嵌合抗原受体T细胞相比,信号激活更温和,更持久。TCR-T细胞疗法是癌症细胞免疫疗法的另一个活跃领域。
方法:我们以前开发了人抗CD19抗体(ET190L1),并产生了新的CD19特异性γ/δTCR-T细胞,ET019003,通过将ET190L1的Fab片段与γ/δTCR恒定链融合,并添加ET190L1-scFv/CD28共刺激分子。在临床前研究中测试ET019003细胞,随后进行1期临床试验。
结果:ET019003细胞产生的细胞因子较少,但在体内和体外仍保持与ET190L1-CAR-T细胞相当的抗肿瘤效力。在第一次人体试验中,8例复发或难治性DLBCL患者接受了治疗.在三名(37.5%)患者中观察到1级CRS;在一名(12.5%)患者中发现了3级ICANS。ET019003输注后血清细胞因子的升高几乎是适度的。中位随访时间为34个月(6-38个月),7例(87.5%)患者获得临床缓解,6例(75%)患者获得完全缓解(CR).操作系统,3年PFS和DOR分别为75.0%,62.5%,71.4%,分别。值得注意的是,1例原发性中枢神经系统淋巴瘤患者在输注后3年内未出现CRS或ICANS,并获得持续CR,在CSF中具有可检测的ET019003细胞。ET019003显示出显著的体内扩张,并且在12个月时在50%的患者中持续存在。三名患者接受了第二次输液,一个用于CR后的巩固治疗,两个用于疾病进展后的挽救治疗,但没有观察到反应。ET019003在第一次输液中扩张惊人,但在第二次输液中效果不佳。
结论:CD19特异性γ/δTCR-T细胞,ET019003具有良好的安全性,可以在复发或难治性DLBCL患者中引起快速反应和持久的CR,甚至原发性中枢神经系统淋巴瘤,为这些患者提供了一种新颖而有效的治疗选择。
背景:NCT04014894。
T cell receptor (TCR)-T cells possess similar effector function, but milder and more durable signal activation compared with chimeric antigen receptor-T cells. TCR-T cell therapy is another active field of cellular immunotherapy for cancer.
We previously developed a human anti-CD19 antibody (ET190L1) and generated novel CD19-specific γ/δ TCR-T cells, ET019003, by fusing the Fab fragment of ET190L1 with γ/δ TCR constant chain plus adding an ET190L1-scFv/CD28 co-stimulatory molecule. ET019003 cells were tested in preclinical studies followed by a phase 1 clinical trial.
ET019003 cells produced less cytokines but retained comparable antitumor potency than ET190L1-CAR-T cells in vivo and in vitro. In the first-in-human trial, eight patients with relapsed or refractory DLBCL were treated. CRS of grade 1 was observed in three (37.5%) patients; ICANS of grade 3 was noted in one (12.5%) patient. Elevation of serum cytokines after ET019003 infusion was almost modest. With a median follow-up of 34 (range 6-38) months, seven (87.5%) patients attained clinical responses and six (75%) achieved complete responses (CR). OS, PFS and DOR at 3 years were 75.0%, 62.5%, and 71.4%, respectively. Notably, patient 1 with primary CNS lymphoma did not experience CRS or ICANS and got an ongoing CR for over 3 years after infusion, with detectable ET019003 cells in CSF. ET019003 showed striking in vivo expansion and persisted in 50% of patients at 12 months. Three patients received a second infusion, one for consolidation therapy after CR and two for salvage therapy after disease progression, but no response was observed. ET019003 expansion was striking in the first infusion, but poor in the second infusion.
CD19-specific γ/δ TCR-T cells, ET019003, had a good safety profile and could induce rapid responses and durable CR in patients with relapsed or refractory DLBCL, even primary CNS lymphoma, presenting a novel and potent therapeutic option for these patients.
NCT04014894.