State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Early Drug Development Centre, Peking University Cancer Hospital & Institute, Beijing, China.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Early Drug Development Centre, Peking University Cancer Hospital & Institute, Beijing, China.
Nat Med. 2024 Aug;30(8):2224-2234. doi: 10.1038/s41591-024-03037-z. Epub 2024 Jun 3.
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, six with 3.75 × 10 and three with 5.0 × 10 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 .
Claudin18.2 (CLDN18.2) 在各种恶性肿瘤的发展中高度表达，特别是胃肠道癌症，并正在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，其 CT041-CG4006 试验的中期结果于 2022 年 6 月公布。在此，我们报告了这项单臂、开放标签、I 期试验的最终结果，该试验评估了 satri-cel 在 CLDN18.2 阳性晚期胃肠道癌症患者中的安全性和疗效。该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（共 83 例）：队列 1，61 例标准化疗难治性胃肠道癌症患者接受 satri-cel 单药治疗；队列 2，15 例标准化疗难治性胃肠道癌症患者接受 satri-cel 联合抗 PD-1 治疗；队列 3，5 例一线治疗后接受 satri-cel 序贯治疗的胃肠道癌症患者；队列 4，2 例抗 CLDN18.2 单克隆抗体难治性胃癌患者接受 satri-cel 单药治疗。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。共有 98 例患者接受了 satri-cel 输注，其中 89 例接受了 2.5×106、6 例接受了 3.75×106 和 3 例接受了 5.0×106 CAR T 细胞。自单采术后中位随访 32.4 个月（95%置信区间[CI]：27.3，36.5）。未报告剂量限制毒性、治疗相关死亡或免疫效应细胞相关神经毒性综合征。96.9%的患者发生细胞因子释放综合征，均为 1-2 级。8 例（8.2%）患者出现胃黏膜损伤。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）。Satri-cel 在 CLDN18.2 阳性晚期胃肠道癌患者中具有良好的安全性，显示出治疗潜力。临床试验标识符：NCT03874897。
