肿瘤细胞治疗研究
英文原题：Novel CD19-specific γ/δ TCR-T cells in relapsed or refractory diffuse large B-cell lymphoma.
CD19 特异性/TCR-T 细胞 ET019003 具有良好的安全性特征，能够在复发或难治性 DLBCL 患者中诱导快速缓解和持久 CR，甚至包括原发性中枢神经系统淋巴瘤，为这些患者提供了一种新颖且强效的治疗选择。
背景：与CAR-T 细胞相比，T细胞受体（TCR）T细胞具有相似的效应功能，但信号活化较温和且更持久。TCR-T细胞疗法是肿瘤细胞免疫治疗的另一个活跃领域。方法：研究者此前开发了人源抗CD19抗体ET190L1，并将其Fab片段与γ/δ TCR恒定链融合，同时加入ET190L1-scFv/CD28共刺激分子，构建新型CD19特异性γ/δ TCR-T细胞ET019003。ET019003细胞先接受临床前研究，随后进入I期临床试验。结果：与ET190L1-CAR-T细胞相比，ET019003细胞产生的细胞因子较少，但在体内外保持了相当的抗肿瘤效力。在首次人体试验中，8名复发或难治性弥漫大B细胞淋巴瘤（DLBCL）患者接受治疗。3名（37.5%）患者出现1级CRS；1名（12.5%）患者出现3级免疫效应细胞相关神经毒性综合征（ICANS）。ET019003输注后血清细胞因子升高幅度总体较小。中位随访34个月（范围6–38个月）时，7名（87.5%）患者获得临床缓解，6名（75%）达到完全缓解（CR）。3年总生存率（OS）、无进展生存率（PFS）和缓解持续时间（DOR）分别为75.0%、62.5%和71.4%。值得注意的是，原发性中枢神经系统淋巴瘤患者1未发生CRS或ICANS，输注后维持CR超过3年，并在脑脊液（CSF）中检测到ET019003细胞。ET019003在体内显著扩增，并在50%的患者体内持续存在至12个月。3名患者接受第二次输注：1名在CR后接受巩固治疗，2名在疾病进展后接受挽救治疗，但均未观察到缓解。ET019003在首次输注后扩增显著，第二次输注后的扩增则较差。结论：CD19特异性γ/δ TCR-T细胞ET019003安全性良好，可使复发或难治性DLBCL患者（包括原发性中枢神经系统淋巴瘤患者）快速缓解并获得持久CR，为这类患者提供了一种新型且有效的治疗选择。试验注册号：NCT04014894。
BACKGROUND: 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. METHODS: We previously developed a human anti-CD19 antibody (ET190L1) and generated novel CD19-specific / TCR-T cells, ET019003, by fusing the Fab fragment of ET190L1 with / 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. RESULTS: 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. CONCLUSIONS: CD19-specific / 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. TRIAL REGISTRATION: NCT04014894.
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