Glypican-3（GPC3）是一种已经被充分了解的与肝细胞癌（HCC）相关的抗原，也是HCC治疗的一个有前景的靶点。CT017 CAR T细胞被工程化，同时表达CAR-GPC3和运行相关转录因子3（RUNX3），这触发了CD8阳性T细胞浸润至癌症微环境。本单中心、单臂、开放标签、I期临床研究招募了2019年8月至2020年12月之间GPC3阳性HCC病人（NCT03980288），这些病人均为治疗失败的重度病例。病人接受250 × 106 个CT017 CAR T细胞剂量的治疗。主要研究目标为评估这个首次应用于人类的产品的安全性和耐受性。共有6名病人接受了7次输注（其中一名病人接受了2次输注），剂量为250 × 106 个细胞。3名病人接受了CT017单药治疗，3名病人在第一次输注时接受了CT017 - 酪氨酸激酶抑制剂（TKI）联合疗法。一名病人在CT017单药治疗后的第二次输注时接受了CT017 - TKI联合疗法。所有病人都经历了细胞因子释放综合征（CRS），其中50%（3/6）为二级，50%（3/6）为三级，所有事件在治疗后得到缓解。未观察到免疫效应细胞相关的神经毒性综合征。由于研究者的安全考虑，剂量递增未进行。在六个可评估的病人中，有一名病人达到了部分缓解，两名病人疾病稳定，目标反应率为16.7%，疾病控制率为50%，无进展生存中位数为3.5个月，疾病控制持续时间中位数为3.2个月，总生存中位数为7.9个月（随访中位数为7.87个月）。最长的总生存期为CT017输注后的18.2个月。当前初步的I期数据显示CT017具有可控的安全性和有希望的抗肿瘤活性，但这些结果需要在一个可靠的临床试验中进行验证。本研究由CARsgen Therapeutics Co., Ltd提供资助。© 2023 作者

Glypican-3 (GPC3) is a well-characterized hepatocellular carcinoma (HCC)-associated antigen and a promising target for HCC treatment. CT017 CAR T cells were engineered to co-express CAR-GPC3 and runt-related transcription factor 3 (RUNX3), which triggers CD8+ T-cell infiltration into the cancer microenvironment.This single-center, single-arm, open-label, phase I clinical study enrolled heavily pretreated patients with GPC3-positive HCC between August 2019 and December 2020 (NCT03980288). Patients were treated with CT017 CAR T cells at a dose of 250 × 106 cells. The primary objective was to assess the safety and tolerability of this first-in-human product.Six patients received 7 infusions (one patient received 2 infusions) at the 250 × 106 cells dose. Three patients received CT017 monotherapy, and three patients received CT017-tyrosine kinase inhibitor (TKI) combination therapy at the first infusion. One patient received CT017-TKI combination therapy at the second infusion after CT017 monotherapy. All patients experienced cytokine release syndrome (CRS), with 50% (3/6) at Grade 2, 50% (3/6) at Grade 3, and all events resolved after treatment. No immune effector cell-associated neurotoxicity syndrome was observed. Dose escalation was not performed due to the investigator's decision regarding safety. Of six evaluable patients, one achieved partial response and two had stable disease for a 16.7% objective response rate, 50% disease control rate, 3.5-month median progression-free survival, 3.2-month median duration of disease control, and 7.9-month median overall survival (OS) with 7.87-month median follow-up. The longest OS was 18.2 months after CT017 infusion.Current preliminary phase I data showed a manageable safety profile and promising antitumor activities of CT017 for patients with advanced HCC. These results need to be confirmed in a robust clinical trial.This study was funded by CARsgen Therapeutics Co., Ltd.© 2023 The Author(s).