On-target/off-tumor toxicities following infusion of low-affinity Nectin-4-specific CAR T cells

Nectin-4 is highly expressed across multiple solid tumor types, and Nectin-4-targeting antibody-drug conjugates have demonstrated promising clinical efficacy. However, the potential of Nectin-4 as a CAR T cell target remains largely unexplored in clinical settings. In this study, we identified multiple Nectin-4-specific antibodies from a fully human phage library and developed corresponding chimeric antigen receptors (CARs). Comprehensive in vitro and in vivo studies revealed that CT293 outperformed other candidates, exhibiting enhanced multifunctionality and superior antitumor activity. Notably, CT293, derived from a low-affinity antibody, exhibited no detectable binding to tumor-produced soluble Nectin-4 (sNectin-4) and demonstrated a higher responsiveness threshold compared with its high-affinity counterpart. Clinically, we initiated a first-in-human clinical trial to evaluate the safety profile of CT293 ( NCT06724835 ). Here, we report a case of classic Nectin-4-targeted treatment-associated on-target/off-tumor toxicities following the infusion of CT293 CAR T cells. We provide a detailed characterization of toxicity progression and corresponding clinical management strategies, identifying dermatologic, oromucosal, and gastrointestinal toxicities as the most clinically significant adverse events. Despite Nectin-4 being a valuable drug target, our study underscores the necessity of systematic risk assessment in the development of Nectin-4-targeted cell therapies.