肿瘤细胞治疗研究
英文原题：Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial final results.
本试验包括剂量递增阶段（n = 15）和四个不同队列的剂量扩展阶段（总 n = 83）：队列1，satri-cel 单药治疗61例标准化疗难治性胃肠道癌症患者；
随着多种恶性肿瘤的发展，尤其是胃肠道癌症中，Claudin18.2（CLDN18.2）呈高表达，正成为癌症治疗的新靶点。Satricabtagene autoleucel（satri-cel）/CT041 是一种靶向 CLDN18.2 的自体嵌合抗原受体（CAR）T 细胞疗法；CT041-CG4006 试验中期结果于 2022 年 6 月公布。本文报告该单臂、开放标签 I 期试验的最终结果，评估 satri-cel 治疗 CLDN18.2 阳性晚期胃肠道癌症患者的安全性和疗效。试验包括剂量递增阶段（n=15）和四个队列的剂量扩展阶段（总 n=83）：队列 1 为 61 例标准化疗难治胃肠癌患者接受 satri-cel 单药；队列 2 为 15 例此类患者接受 satri-cel 联合抗 PD-1 治疗；队列 3 为 5 例胃肠癌患者一线治疗后序贯接受 satri-cel；队列 4 为 2 例抗 CLDN18.2 单克隆抗体难治胃癌患者接受 satri-cel 单药。主要终点为安全性；次要终点包括疗效、药代动力学和免疫原性。共 98 例患者接受 satri-cel 输注，其中 89 例剂量为 2.5×10^8 个 CAR T 细胞，6 例为 3.75×10^8 个，3 例为 5.0×10^8 个。自单采起中位随访 32.4 个月（95% CI：27.3–36.5）。未报告剂量限制性毒性、治疗相关死亡或免疫效应细胞相关神经毒性综合征。96.9% 患者发生细胞因子释放综合征，均为 1–2 级。8 例（8.2%）患者发现胃黏膜损伤。全部 98 例患者的总缓解率和疾病控制率分别为 38.8% 和 91.8%；中位无进展生存期和总生存期分别为 4.4 个月（95% CI：3.7–6.6）和 8.8 个月（95% CI：7.1–10.2）。Satricel 对 CLDN18.2 阳性晚期胃肠道癌症患者显示治疗潜力，且安全性可控。ClinicalTrials.gov 注册号：NCT03874897。
Claudin18.2 (CLDN18.2) is highly expressed with the development of various malignant tumors, especially gastrointestinal cancers, and is emerging as a new target for cancer treatment. Satricabtagene autoleucel (satri-cel)/CT041 is an autologous chimeric antigen receptor (CAR) T cell targeting CLDN18.2, and the interim results of the CT041-CG4006 trial were reported in June 2022. Here we present the final results of this single-arm, open-label, phase 1 trial, which evaluated the safety and efficacy of satri-cel in patients with CLDN18.2-positive advanced gastrointestinal cancers. This trial included a dose-escalation stage (n = 15) and a dose-expansion stage in four different cohorts (total n = 83): cohort 1, satri-cel monotherapy in 61 patients with standard chemotherapy-refractory gastrointestinal cancers; cohort 2, satri-cel plus anti-PD-1 therapy in 15 patients with standard chemotherapy-refractory gastrointestinal cancers; cohort 3, satri-cel as sequential treatment after first-line therapy in five patients with gastrointestinal cancers; and cohort 4, satri-cel monotherapy in two patients with anti-CLDN18.2 monoclonal antibody-refractory gastric cancer. The primary endpoint was safety; secondary endpoints included efficacy, pharmacokinetics and immunogenicity. A total of 98 patients received satri-cel infusion, among whom 89 were dosed with 2.5 10 8 , six with 3.75 10 8 and three with 5.0 10 8 CAR T cells. Median follow-up was 32.4 months (95% confidence interval (CI): 27.3, 36.5) since apheresis. No dose-limiting toxicities, treatment-related deaths or immune effector cell-associated neurotoxicity syndrome were reported. Cytokine release syndrome occurred in 96.9% of patients, all classified as grade 1-2. Gastric mucosal injuries were identified in eight (8.2%) patients. The overall response rate and disease control rate in all 98 patients were 38.8% and 91.8%, respectively, and the median progression-free survival and overall survival were 4.4 months (95% CI: 3.7, 6.6) and 8.8 months (95% CI: 7.1, 10.2), respectively. Satri-cel demonstrates therapeutic potential with a manageable safety profile in patients with CLDN18.2-positive advanced gastrointestinal cancer. ClinicalTrials.gov identifier: NCT03874897 .
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