GPC3-specific TCR-engineered T-cells from a vaccine responder show potent antitumor activity against HLA-A2-positive cancers.

Hepatocellular carcinoma (HCC) and hepatoblastoma are aggressive cancers with limited effective treatments, especially for metastatic disease. Glypican-3 (GPC3) is an attractive immunotherapeutic target due to its high expression in these malignancies and minimal presence in healthy adult tissues. While GPC3 peptide vaccines have shown some promise, they often suffer from limited epitope coverage and weak immunogenicity. This study addresses the need for more potent and specific GPC3-targeted immunotherapies, leveraging the success of T-cell receptor (TCR)-engineered T-cell therapy.

Researchers isolated high-avidity T-cell receptors (TCRs) from cytotoxic T lymphocyte (CTL) clones. These clones were established from a pediatric hepatoblastoma patient who achieved long-term recurrence-free survival after GPC3 peptide vaccination. Using a retroviral vector designed for endogenous TCR suppression, these TCR genes were introduced into primary human T cells to generate GPC3-specific TCR-T cells. The engineered cells were then evaluated for GPC3-specific recognition and cytotoxicity against GPC3-positive tumor cells in vitro. Their antitumor efficacy was further assessed in xenograft models to observe effects on tumor engraftment and growth.