T-cell receptor-engineered T-cell therapy using a glypican-3-specific TCR derived from a hepatoblastoma vaccine responder for HLA-A2-positive glypican-3-expressing cancers.
The study generated HLA-A*02:01-restricted, GPC3-specific TCR-engineered human T cells from a long-term hepatoblastoma vaccine responder and reports selective in-vitro cytotoxicity plus antitumor activity in xenograft models.
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The study generated HLA-A*02:01-restricted, GPC3-specific TCR-engineered human T cells from a long-term hepatoblastoma vaccine responder and reports selective in-vitro cytotoxicity plus antitumor activity in xenograft models.
Research significance
The supplied evidence shows antigen- and HLA-restricted preclinical activity; it supports—but does not clinically establish—the hypothesis that these TCR-T cells could treat HLA-A*02-positive, GPC3-expressing tumors, including refractory hepatoblastoma.
Source abstract
Glypican-3 (GPC3) is highly expressed in most hepatocellular carcinomas (HCCs) and hepatoblastoma, shows minimal expression in non-tumor adult tissues, and is also detected in several other malignancies, making it an ideal target for anticancer immunotherapy. We previously demonstrated in clinical trials that GPC3 peptide vaccination can induce durable antitumor immunity in patients with HCC and pediatric hepatoblastoma and established human leukocyte antigen (HLA)-A∗02:01-restricted GPC3-specific cytotoxic T lymphocyte (CTL) clones. In this study, we isolated high-avidity T-cell receptors (TCRs) from CTL clones established from a pediatric hepatoblastoma patient who achieved long-term recurrence-free survival for more than 10 years after surgical resection of pulmonary metastases followed by GPC3 peptide vaccination. Using a retroviral vector incorporating endogenous TCR suppression, these TCR genes were introduced into primary human T cells to generate GPC3-specific TCR-engineered T cells (TCR-T cells). These TCR-T cells exhibited GPC3-specific recognition and significant cytotoxicity against GPC3-positive tumor cells in vitro, while showing minimal activity against GPC3-negative targets. Moreover, GPC3-specific TCR-T cells migrated to tumor sites, resulting in the prevention of tumor engraftment as well as tumor growth suppression and stabilization in xenograft models. GPC3-targeted TCR-T cells derived from CTLs induced by GPC3 peptide vaccination demonstrated potent antitumor activity against HLA-A∗02-positive and GPC3-positive cancers. These findings provide an important rationale for Phase I clinical trials of GPC3-targeted TCR-T cells as a promising therapeutic strategy for GPC3-expressing solid tumors, including HCC and refractory hepatoblastoma.