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Updated: Jul 17, 2026
A GPC3-targeting Bispecific Antibody, GPC3-S-Fab, with Potent Cytotoxicity
Published on: July 12, 2018
GPC3-specific dnTGFβRII-armoured CAR T cells for hepatocellular carcinoma
Qi Zhang1,2,3,4,5, Qihan Fu2,3,5,6, Yinan Shen1,2,3
1Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Abstract:
Glypican-3 (GPC3) is highly expressed in hepatocellular carcinoma (HCC), making it an attractive target for chimeric antigen receptor (CAR) T cell therapy; however, this approach has previously shown limited clinical efficacy, potentially owing to high levels of transforming growth factor-β (TGFβ) in the tumour microenvironment1-4. We therefore engineered CAR T cells with a dominant-negative TGFβ receptor II, which showed enhanced antitumour activity in preclinical studies5. Here we report findings from a first-in-human trial evaluating the safety and efficacy of C-CAR031 in patients with advanced, treatment-refractory HCC ( NCT05155189 ). Thirty-six patients received CAR T infusions at four dose levels (from 0.75 × 106 to 4.0 × 106 cells per kg). Cytokine release syndrome was reported in 34 patients, of which two cases were grade 3. Nine patients had non-haematological adverse events of grade 3 or higher. Tumour regression was observed in 32 patients, with a median best tumour reduction from baseline of 41.6% (range: 3.4-94.4%) in target lesions. The objective response rate was 44.4%, and the median duration of response was 4.4 months (95% confidence interval: 2.9-7.4). Median progression-free survival and overall survival were 4.2 months (95% confidence interval: 2.9-4.8) and 14.2 months (95% confidence interval: 10.1 to not evaluable), respectively. High-throughput analyses of tumour samples and functional validation suggested that GPC3 antigen loss and increased TGFβ levels may contribute to C-CAR031 resistance. Collectively, these results indicate that C-CAR031 has a manageable safety profile and encouraging antitumour activity in heavily pretreated patients with advanced HCC.
Insights
This first-in-human trial of C-CAR031 in advanced liver cancer showed promising tumor reduction and survival rates. Engineered CAR T cells targeting Glypican-3 (GPC3) demonstrated manageable safety, offering hope for treatment-refractory hepatocellular carcinoma (HCC).
Area of Science:
- Immunotherapy
- Oncology
- Biotechnology
Background:
- Hepatocellular carcinoma (HCC) expresses Glypican-3 (GPC3), a target for CAR T cell therapy.
- Previous GPC3-targeted CAR T cell therapy showed limited efficacy due to tumor microenvironment factors like TGFβ.
- Engineered CAR T cells with a dominant-negative TGFβ receptor II (C-CAR031) were developed to overcome resistance.
Purpose of the Study:
- To evaluate the safety and efficacy of C-CAR031 in patients with advanced, treatment-refractory HCC.
- To assess tumor response, survival outcomes, and adverse events associated with C-CAR031 therapy.
Main Methods:
- A first-in-human Phase I trial (NCT05155189) involving 36 patients with advanced HCC.
- Patients received C-CAR031 CAR T cell infusions at escalating dose levels.
- Tumor samples were analyzed using high-throughput methods to identify resistance mechanisms.
Main Results:
- Tumor regression was observed in 32 patients, with a median best reduction of 41.6%.
- Objective response rate was 44.4%, with median progression-free survival of 4.2 months and overall survival of 14.2 months.
- Cytokine release syndrome occurred in 34 patients; two were grade 3. Nine patients experienced grade 3+ non-hematological adverse events.
Conclusions:
- C-CAR031 demonstrates a manageable safety profile and encouraging anti-tumor activity in heavily pretreated advanced HCC patients.
- GPC3 antigen loss and increased TGFβ levels were identified as potential mechanisms of resistance.
- This engineered CAR T cell therapy represents a promising approach for advanced HCC, warranting further investigation.
