Systemic delivery of cadherin 17–specific CAR T cells allows effective and safe targeting of colorectal cancer liver metastases

Liver metastases represent the leading cause of death in patients with colorectal cancer (CRC). Chimeric antigen receptor (CAR) T cell therapy holds promise in this context, but any effort to bring it to the bedside requires careful antigen selection and testing in clinically relevant models. Here, we identified cadherin-17 (CDH17) as a candidate antigen for CAR T cell therapy of CRC liver metastases. We hence designed human CDH17 CARs differing in antigen binding and extracellular spacer regions and compared the different constructs in preclinical models of antitumor efficacy, cytokine release syndrome, and on-target off-tumor toxicity. Whereas the binding domains differed in efficacy in vitro, the spacer region shaped the kinetics of the CAR T cells in vivo. When used in a CRC liver xenograft model, CDH17 CAR T cells efficiently suppressed tumor growth upon either systemic or locoregional administration. However, when tested in mice reconstituted with a human immune system, CAR T cells injected locally caused a particularly harsh cytokine release syndrome. Confocal microscopy revealed that CDH17 is exposed on the entire surface of tumor cells, whereas its expression in healthy colon is restricted to lateral junctions between epithelial cells. Accordingly, CDH17 CAR T cells showed dose-dependent cytokine release in response to CRC tissue slices while displaying no reaction against healthy colon tissue samples. Overall, these findings support systemic delivery of CDH17 CAR T cells as a safe and effective approach to treat CRC liver metastases and pave the way for a phase 1/2 clinical trial.

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Publication Details

Journal
Science Translational Medicine
Published
2025-05-28
DOI
https://doi.org/10.1126/scitranslmed.adr1928
Citations
3
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
3.14
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article

Systemic delivery of cadherin 17–specific CAR T cells allows effective and safe targeting of colorectal cancer liver metastases

Laura Falcone, Marta Angiola Moresco, Federica Ungaro, Laura Perani et al.
3 citations
Science Translational Medicine
CAR-T cell therapy research
3.14
article

Systemic delivery of cadherin 17–specific CAR T cells allows effective and safe targeting of colorectal cancer liver metastases

Laura Falcone, Marta Angiola Moresco, Federica Ungaro, Laura Perani, Camilla Sirini, Fabio Ciceri, Rita El Khoury, Chiara Balestrieri, Claudio Doglioni, Giovanni Tonon, Emmanuel Donnadieu, Béatrice Gréco, Alice Bergamini, Edoardo Campodonico, Oronza A. Botrugno, Federica De Girardi, Monica Casucci, Chiara Bonini, Elena Tiziano, Amanda Facoetti, Barbara Camisa, Laura Rossi, Alice Machado, Giulio Giovannoni, Katia Palmisano
article en
3 citations

Abstract

Liver metastases represent the leading cause of death in patients with colorectal cancer (CRC). Chimeric antigen receptor (CAR) T cell therapy holds promise in this context, but any effort to bring it to the bedside requires careful antigen selection and testing in clinically relevant models. Here, we identified cadherin-17 (CDH17) as a candidate antigen for CAR T cell therapy of CRC liver metastases. We hence designed human CDH17 CARs differing in antigen binding and extracellular spacer regions and compared the different constructs in preclinical models of antitumor efficacy, cytokine release syndrome, and on-target off-tumor toxicity. Whereas the binding domains differed in efficacy in vitro, the spacer region shaped the kinetics of the CAR T cells in vivo. When used in a CRC liver xenograft model, CDH17 CAR T cells efficiently suppressed tumor growth upon either systemic or locoregional administration. However, when tested in mice reconstituted with a human immune system, CAR T cells injected locally caused a particularly harsh cytokine release syndrome. Confocal microscopy revealed that CDH17 is exposed on the entire surface of tumor cells, whereas its expression in healthy colon is restricted to lateral junctions between epithelial cells. Accordingly, CDH17 CAR T cells showed dose-dependent cytokine release in response to CRC tissue slices while displaying no reaction against healthy colon tissue samples. Overall, these findings support systemic delivery of CDH17 CAR T cells as a safe and effective approach to treat CRC liver metastases and pave the way for a phase 1/2 clinical trial.

Science Translational MedicineVol. 17(800)
Université Paris-Sud (FR), Centre National de la Recherche Scientifique (FR), Vita-Salute San Raffaele University (IT), Inserm (FR), Université Paris Cité (FR), Université Paris-Saclay (FR), La Ligue Contre le Cancer (FR), Institut Cochin (FR), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT)
Good health and well-being
Openalex Percentile: Top 8%
CAR-T cell therapy research
3.14
DOISourceOpenAlex
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