Phase I Trial of GPC3-Targeted TCR Fusion Construct, CT0180, in Patients with Advanced Hepatocellular Carcinoma

Abstract Purpose: Treatment options for advanced hepatocellular carcinoma (HCC) remain limited, and responses to later-line therapies are modest. Glypican 3 (GPC3), highly expressed in HCC but rarely in normal tissues, is an attractive tumor-specific target. CT0180 is a GPC3-targeted single-chain fragment variable linked to CD3ε designed to integrate into the native T-cell receptor (TCR) complex and activate full TCR signaling upon GPC3 binding. Patients and Methods: In this open-label, dose-escalation phase I trial, patients with advanced GPC3-positive HCC that had progressed on or were intolerant to standard therapies received CT0180 after fludarabine/cyclophosphamide lymphodepletion. The study objectives were safety, preliminary efficacy, and cellular pharmacokinetics. Single-cell RNA sequencing (scRNA-seq) and TCR sequencing were used to profile immune reconstitution. Results: Seven patients received 15 infusions across 4 dose levels (DL): 1 × 107 (n = 1), 3 × 107 (n = 1), 1 × 108 (n = 3), and 3 × 108 (n = 2) cells. Grade 3 to 4 adverse events were primarily hematologic. Cytokine release syndrome occurred in 85.7% of patients, all grade 1 with no dose-limiting toxicities or immune effector cell–associated neurotoxicity observed. Two patients (at DL2 and DL4) achieved partial responses, and 3 (at DL1, DL3, and DL4) achieved stable disease, yielding an objective response rate of 28.6% and a disease control rate of 71.4%. The median progression-free survival and overall survival were 7.6 and 11.6 months, respectively. scRNA-seq revealed baseline NK-cell enrichment in patients with clinical benefit and sustained cytotoxic CD8 effector expansion after repeat infusion. Conclusions: CT0180 demonstrated a preliminary manageable safety profile and clinical activity in heavily pretreated HCC, supporting further clinical evaluation.