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. 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 four dose levels (DLs): 1×10⁷ (n=1), 3×10⁷ (n=1), 1×10⁸ (n=3), and 3×10⁸ (n=2) cells. Grade 3–4 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 three (at DL1, DL3, and DL4) achieved stable disease, yielding an objective response rate of 28.6% and a disease control rate of 71.4%. Median progression-free 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.
Sun et al. (Thu,) studied this question.