CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
靶向 HBsAg 与 GPC3 的单靶点与双靶点 CAR-T 细胞在 HBV 阳性肝细胞癌中平衡安全性与抗肿瘤疗效
英文原题：Single- and dual-target CAR-T cells targeting HBsAg and GPC3 to balance safety and antitumor efficacy in HBV-positive hepatocellular carcinoma.
查看英文原题
Single- and dual-target CAR-T cells targeting HBsAg and GPC3 to balance safety and antitumor efficacy in HBV-positive hepatocellular carcinoma.
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中文摘要
抗原逃逸和靶向非肿瘤效应限制了嵌合抗原受体（CAR）-T 细胞在实体瘤中的应用。Glypican-3（GPC3）和乙型肝炎病毒（HBV）是肝细胞癌（HCC）中 CAR-T 细胞治疗的两个新兴治疗靶点。
在本研究中，我们构建了针对 HBV 表面抗原（HBsAg）和 GPC3 的单抗原 CAR。HBsAg-CAR-T 特异性靶向 HBV 阳性 HCC 细胞，显示出优于 GPC3-CAR-T 的抗肿瘤活性。
然而，由于 HBsAg 在非恶性肝细胞中的膜定位，HBsAg-CAR-T 对非肿瘤肝细胞溶解的脱靶问题引发了担忧。此外，在约 27% 的受检 HCC 患者中，HBsAg 和 GPC3 呈异质性表达。为应对这些挑战，我们开发了双顺反子 HBsAg-GPC3-CAR-T 细胞，其可选择性地识别双阳性 HCC 细胞，从而降低脱靶毒性。在异质性 HCC 细胞和患者来源异种移植（PDX）HCC 移植瘤中，HBsAg-CAR-T 与 GPC3-CAR-T 细胞联合给药展现出优于单种 CAR-T 使用的抗癌疗效。
我们的研究凸显了 HBsAg/GPC3 双 CAR 方法在提高 HCC 治疗疗效和安全性方面的潜力。
展开英文摘要原文
Antigen-escape and on-target off-tumor effects limit the application of chimeric antigen receptor (CAR)-T cells in solid tumors. Glypican-3 (GPC3) and hepatitis B virus (HBV) are two emerging therapeutic targets for CAR-T cell therapy in hepatocellular carcinoma (HCC). In this study, we generated single-antigen CARs against HBV surface antigen (HBsAg) and GPC3. HBsAg-CAR-T specifically targeted HBV-positive HCC cells, showing superior antitumor activity compared to GPC3-CAR-T.
However, concerns arose about off-tumor liver cytolysis by HBsAg-CAR-T due to the membrane localization of HBsAg in non-malignant liver cells.
Moreover, HBsAg and GPC3 were heterogeneously expressed in approximately 27 percent of tested patients with HCC. To address these challenges, we developed bicistronic HBsAg-GPC3-CAR-T cells that selectively recognized double-positive HCC cells, thereby reducing off-tumor toxicity. Co-administration of HBsAg-CAR-T and GPC3-CAR-T cells exhibited superior anticancer efficacy over single CAR-T use in heterogeneous HCC cells and patient-derived xenograft (PDX) HCC xenografts.
Our study highlights the potential of HBsAg/GPC3 dual-CAR approaches to enhance therapeutic outcomes and safety in HCC treatment.
论文信息
- 作者
- Chen Q、Chen Z、Xu D、Wang H、Hu A、Hu Z、Gao P、Li H
- 单位
- Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu Province 221000, China.China
- 期刊
- iScience2026 Aug 21
- 原文标识
- PubMed 42495521 · DOI 10.1016/j.isci.2026.116844