GPC3-specific dnTGFβRII-armoured CAR T cells for hepatocellular carcinoma.

Authors

Qi Zhang, Qihan Fu, Yinan Shen, Wanyue Cao, Gaowei Jin, Yize Zhang, Jiangchao Wu, Cao Chen, Hongkan Wang, Xingyuan Xu, Ke Sun, Xing Xue, Attilio Bondanza, Daisy Cao, Nina Chu, Nick Durham, Mark Cobbold, Benedetto Farsaci, Maria Letizia Giardino Torchia, Yixin Hao, Yi Hong, Jiaqi Huang, Michael Humphries, Qijie Jian, Gordon Moody, John Stone, Lingyan Sun, Eric Tu, Fei Wang, Fuzhe Wang, Ye Yang, Yihong Yao, Andy Zou, Xueli Bai, Tingbo Liang

Published in

Nature. Jul 15, 2026. Epub Jul 15, 2026.

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 microenvironment^1-4. 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.

PMID:
42457964
Bibliographic data and abstract were imported from PubMed on 16 Jul 2026.

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