浙江大学梁廷波课题组的一项最新研究提出了靶向GPC3的显性负性TGFβ受体II装甲CAR-T细胞治疗肝细胞癌。相关论文发表在2026年7月15日出版的《自然》杂志上。

因此，该研究组设计了具有显性阴性TGFβ受体II的CAR - T细胞，其在临床前研究中显示出增强的抗肿瘤活性。

在此，小组报告了一项首次人体试验的结果，该试验评估了C-CAR031在晚期难治性HCC患者中的安全性和有效性（NCT05155189）。共36例患者接受了四个剂量水平（0.75×10⁶至4.0×10⁶个细胞/公斤体重）的CAR-T输注。34例患者出现细胞因子释放综合征，其中2例为3级。9例患者发生3级或更高级别的非血液学不良事件。32例患者观察到肿瘤缩小，靶病灶较基线缩小的中位最佳幅度为41.6%（范围：3.4%–94.4%）。客观缓解率为44.4%，中位缓解持续时间为4.4个月（95%置信区间：2.9–7.4）。中位无进展生存期和总生存期分别为4.2个月（95%置信区间：2.9–4.8）和14.2个月（95%置信区间：10.1至不可评估）。

肿瘤样品的高通量分析和功能验证表明，GPC3抗原丢失和TGFβ水平升高可能有助于C-CAR031耐药性。总的来说，这些结果表明C-CAR031具有可管理的安全性，并且在重度预处理的晚期HCC患者中具有抗肿瘤活性。

据悉，Glypican-3 （GPC3）在肝细胞癌（HCC）中高度表达，使其成为嵌合抗原受体（CAR） T细胞治疗的一个有吸引力的靶点；然而，这种方法先前显示出有限的临床疗效，可能是由于肿瘤微环境中高水平的转化生长因子-β (TGFβ) 。

附：英文原文

Title: GPC3-specific dnTGFβRII-armoured CAR T cells for hepatocellular carcinoma

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

Issue&Volume: 2026-07-15

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 microenvironment1,2,3,4. 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.

DOI: 10.1038/s41586-026-10786-z

Source: https://www.nature.com/articles/s41586-026-10786-z