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

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, 3.5-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. Interpretation 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. Funding This study was funded by CARsgen Therapeutics Co., Ltd.