ArticleiScience2026
Single- and dual-target CAR-T cells targeting HBsAg and GPC3 to balance safety and antitumor efficacy in HBV-positive hepatocellular carcinoma.
Article in iScience, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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21 authors.
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Abstract
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.
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