- Homogeneous overexpression of B7-H3 in intrahepatic cholangiocarcinoma identifies it as a promising therapeutic target.
- iCas9.B7-H3 CAR T cells demonstrated potent in vitro cytotoxicity against multiple patient-derived ICC cell lines and organotypic tumour spheroids.
- Single systemic dose eradicated orthotopic ICC in mice with durable remission and resistance to tumour re-challenge; splenic or intratumoural delivery was equally effective.
J Exp Clin Cancer Res. 2026 Jun 4. doi: 10.1186/s13046-026-03723-5. Online ahead of print.
ABSTRACT
BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver tumor, with an increasing incidence over the past two decades. While surgery offers a curative option, most patients present with advanced disease, for which current therapeutic options are ineffective. B7-H3 is an immune checkpoint molecule that is overexpressed in ICC relative to normal tissue, making it an attractive therapeutic target. Utilizing in vitro and in vivo models, we investigated the efficacy of a B7-H3-targeted CAR T to treat ICC.
METHODS: B7-H3 CAR T cells were generated from peripheral blood mononuclear cells of normal donors, transduced with a retroviral vector encoding a second generation B7-H3 specific CAR construct, incorporating an inducible caspase9 (iCas9) suicide gene-based safety switch. The anti-tumor activity of iCas9.B7-H3 CAR T cells against ICC was tested in vitro using human ICC cell lines and patient-derived organotypic tumor spheroids (PDOTS) and in vivo using xenograft models of ICC.
RESULTS: Human ICC cell lines, resected ICC samples from patients, and ICC tissue microarrays demonstrate homogeneous expression of B7-H3. iCas9.B7-H3 CAR T cells demonstrated potent anti-tumor activity in vitro against multiple patient-derived ICC cell lines. A single systemic dose of iCas9.B7-H3 CAR T cells induced complete and sustained eradication of orthotopic ICC tumors in a preclinical mouse model, even after tumor re-challenge. Locoregional delivery of CAR T cells via splenic and intra-tumoral injection was equally effective as systemic therapy.
CONCLUSIONS: These results provide a strong rationale for evaluating the iCas9.B7-H3 CAR T cell strategy in clinical trials for patients with advanced ICC.
PMID:42243894 | DOI:10.1186/s13046-026-03723-5
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