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Updated: Aug 5, 2026
A GPC3-targeting Bispecific Antibody, GPC3-S-Fab, with Potent Cytotoxicity
Published on: July 12, 2018
Phase I Trial of GPC3-Targeted TCR Fusion Construct, CT0180, in patients with Advanced Hepatocellular Carcinoma
Xuqi Sun1, Wanwan Gao2, Chunhui Shou1
1First Affiliated Hospital Zhejiang University Hangzhou, Zhejiang China.
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.
Insights
A novel therapy targeting Glypican-3 (GPC3) showed promising results in advanced hepatocellular carcinoma (HCC). This GPC3-targeted treatment demonstrated manageable safety and clinical activity in heavily pretreated patients.
Area of Science:
- Oncology
- Immunotherapy
- Hepatocellular Carcinoma Research
Background:
- Advanced hepatocellular carcinoma (HCC) has limited treatment options with modest efficacy in later lines of therapy.
- Glypican-3 (GPC3) is a highly expressed HCC-specific target, making it an attractive candidate for novel therapies.
- CT0180 is a GPC3-targeted single-chain fragment variable (scFv) linked to CD3ε, designed to activate T cell receptors (TCRs) upon GPC3 binding.
Purpose of the Study:
- To evaluate the safety, preliminary efficacy, and cellular pharmacokinetics of CT0180 in patients with advanced GPC3-positive HCC.
- To assess immune reconstitution using single-cell RNA sequencing (scRNA-seq) and TCR sequencing.
Main Methods:
- An open-label, dose-escalation Phase I trial was conducted in patients with advanced HCC who progressed on or were intolerant to standard therapies.
- Patients received CT0180 following fludarabine/cyclophosphamide lymphodepletion.
- scRNA-seq and TCR sequencing were employed to analyze immune cell populations and T cell receptor repertoire.
Main Results:
- Seven patients received CT0180 across four dose levels. Grade 3-4 adverse events were primarily hematologic; cytokine release syndrome occurred in 85.7% but was all Grade 1.
- No dose-limiting toxicities or immune effector cell-associated neurotoxicity were observed.
- Objective response rate was 28.6% (2 partial responses) and disease control rate was 71.4% (3 stable disease). Median progression-free survival was 7.6 months and overall survival was 11.6 months. scRNA-seq indicated baseline NK-cell enrichment and sustained CD8 effector expansion in responders.
Conclusions:
- CT0180 demonstrated a preliminary manageable safety profile in heavily pretreated HCC patients.
- The GPC3-targeted therapy showed preliminary clinical activity, including objective responses and disease control.
- Further clinical evaluation of CT0180 is warranted for advanced HCC treatment.
