Shi Donghua, Shi Yaoping, Kaseb Ahmed O, Qi Xingxing, Zhang Yuan, Chi Jiachang, Lu Qing, Gao Huiping, Jiang Hua, Wang Huamao, Yuan Daijing, Ma Hong, Wang Hongyang, Li Zonghai, Zhai Bo
Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Clin Cancer Res. 2020 Aug 1;26(15):3979-3989. doi: 10.1158/1078-0432.CCR-19-3259. Epub 2020 May 5.
Our preclinical studies demonstrated the potential of chimeric antigen receptor (CAR)-glypican-3 (GPC3) T-cell therapy for hepatocellular carcinoma (HCC). We report herein the first published results of CAR-GPC3 T-cell therapy for HCC.
In two prospective phase I studies, adult patients with advanced GPC3 HCC (Child-Pugh A) received autologous CAR-GPC3 T-cell therapy following cyclophosphamide- and fludarabine-induced lymphodepletion. The primary objective was to assess the treatment's safety. Adverse events were graded using the Common Terminology Criteria for Adverse Events (version 4.03). Tumor responses were evaluated using the RECIST (version 1.1).
A total of 13 patients received a median of 19.9 × 10 CAR-GPC3 T cells by a data cutoff date of July 24, 2019. We observed pyrexia, decreased lymphocyte count, and cytokine release syndrome (CRS) in 13, 12, and nine patients, respectively. CRS (grade 1/2) was reversible in eight patients. One patient experienced grade 5 CRS. No patients had grade 3/4 neurotoxicity. The overall survival rates at 3 years, 1 year, and 6 months were 10.5%, 42.0%, and 50.3%, respectively, according to the Kaplan-Meier method. We confirmed two partial responses. One patient with sustained stable disease was alive after 44.2 months. CAR T-cell expansion tended to be positively associated with tumor response.
This report demonstrated the initial safety profile of CAR-GPC3 T-cell therapy. We observed early signs of antitumor activity of CAR-GPC3 T cells in patients with advanced HCC.
我们的临床前研究证明了嵌合抗原受体（CAR）-磷脂酰肌醇蛋白聚糖-3（GPC3）T细胞疗法治疗肝细胞癌（HCC）的潜力。我们在此报告CAR-GPC3 T细胞疗法治疗HCC的首次发表结果。
在两项前瞻性I期研究中，患有晚期GPC3 HCC（Child-Pugh A级）的成年患者在接受环磷酰胺和氟达拉滨诱导的淋巴细胞清除后接受自体CAR-GPC3 T细胞疗法。主要目的是评估治疗的安全性。使用不良事件通用术语标准（第4.03版）对不良事件进行分级。使用RECIST（第1.1版）评估肿瘤反应。
截至2019年7月24日的数据截止日期，共有13名患者接受了中位数为19.9×10的CAR-GPC3 T细胞。我们分别在13例、12例和9例患者中观察到发热、淋巴细胞计数减少和细胞因子释放综合征（CRS）。8例患者的CRS（1/2级）是可逆的。1例患者发生5级CRS。没有患者出现3/4级神经毒性。根据Kaplan-Meier方法，3年、1年和6个月时的总生存率分别为10.5%、42.0%和50.3%。我们确认了2例部分缓解。1例疾病持续稳定的患者在44.2个月后仍存活。CAR T细胞扩增倾向于与肿瘤反应呈正相关。
本报告展示了CAR-GPC3 T细胞疗法的初步安全性概况。我们在晚期HCC患者中观察到了CAR-GPC3 T细胞抗肿瘤活性的早期迹象。
