University of Pennsylvania researchers presented first-in-human phase I data for SynKIR-110, a “KIR-CAR” T cell therapy designed to reduce exhaustion risk in solid tumors. The approach uses a multi-chain architecture modeled on NK cell receptors, separating tumor recognition from activation via an intrinsic on-off mechanism. In the dose-escalation study, nine patients with advanced mesothelin-expressing cancers received therapy after an average of four prior lines. Investigators reported a favorable safety profile alongside early efficacy signals, including disease stabilization in four patients and an ongoing partial response in the highest dose cohort. The program targets solid tumor types that, as presented, reportedly have never had an approved cell therapy. Principal investigator Janos L. Tanyi, MD, PhD, emphasized the design’s intent to avoid continuous activation seen in conventional CAR T constructs. The trial’s early results, while small, add to the growing field of solid-tumor CAR-T reinventions focused on durability and exhaustion control, and it sets a clinical benchmark for how biomarker selection and dose optimization may be handled in follow-on cohorts.