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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 Shou3
1Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 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.
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.
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.
