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

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.