Chaurasiya S; Kim SI; Sah P; Zhang Z; Vashi Y; Wu H; Cillis J; Park A; Yang A; Woo Y; Xiong G; Liu J; Zhang H; Wang P; Liu C; Fong Y · 2026 · Frontiers in immunology
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BACKGROUND: Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality worldwide and is characterized by substantial molecular and immunologic heterogeneity that contributes to therapeutic resistance and poor clinical outcomes. Glypican-3 (GPC3) is an attractive immunotherapy target in HCC; however, its heterogeneous expression limits the effectiveness of GPC3-directed approaches. ECT204, a GPC3-directed ARTEMIS ® T-cell therapy, has shown improved safety compared with conventional CAR T cells but remains dependent on sufficient tumor-associated GPC3 expression. In this study, we investigated whether an oncolytic virus could be used to selectively deliver GPC3 to tumor cells to expand the applicability of GPC3-targeted immunotherapies. METHODS: We engineered the oncolytic vaccinia virus CF33-GPC3 to express GPC3 and evaluated its ability to sensitize GPC3-negative tumor cells to ECT204 in vitro and in vivo using GPC3-knockout HepG2 xenograft models. We also assessed the compatibility with other GPC3-targeted immunotherapies, including a bispecific T-cell engager (BiTE) and the monoclonal antibody codrituzumab. RESULTS: CF33-GPC3 efficiently induced surface expression of GPC3 in previously GPC3-negative tumor cells, resulting in activation of GPC3-directed ECT204 T cells and subsequent tumor cell killing. In vivo, combination therapy with CF33-GPC3 and ECT204, administered either intratumorally or intravenously, achieved significantly greater tumor control than either monotherapy alone. Moreover, OV-mediated GPC3 expression sensitized tumor cells to killing by GPC3-specific BiTE-redirected T cells and enhanced codrituzumab-mediated NK cell cytotoxicity. CONCLUSIONS: These findings demonstrate that OV-mediated GPC3 delivery can overcome antigen heterogeneity in HCC and broaden the applicability of GPC3-directed immunotherapies.
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