RUNX-3-expressing CAR T cells targeting glypican-3 in patients with heavily pretreated advanced hepatocellular carcinoma: a phase I trial

作者：Qihan Fu, Yi Zheng, Weijia Fang, Qingwei Zhao, Peng Zhao, Lulu Liu, You Zhai, Zhou Tong, Hangyu Zhang, Meihua Lin, Xudong Zhu, Huamao Wang, Yumeng Wang, Zhen Liu, Daijing Yuan, Xuanwen Bao, Wanwan Gao, Xiaomeng Dai, Zonghai Li, Tingbo Liang · 发表于：EClinicalMedicine · 年份：2023 · DOI：10.1016/j.eclinm.2023.102175 · 被引用次数：74 · 研究领域：CAR-T cell therapy research、Cancer Immunotherapy and Biomarkers、Immune Cell Function and Interaction

Background 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. Methods 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 × 10 6 cells. The primary objective was to assess the safety and tolerability of this first-in-human product. Findings Six patients received 7 infusions (one patient received 2 infusions) at the 250 × 10 6 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...