ICAM1-targeted Costimulation Extends HER2 CAR T Cytotoxicity to HER2-low and HER2-negative Tumors Through Synergy with TCR Signaling.

Autologous T cells engineered to express a HER2 chimeric antigen receptor (CAR) have shown limited clinical efficacy. To broaden antitumor activity, we co-expressed a chimeric costimulatory receptor (CCR) targeting ICAM1 (ICCR) in HER2 CAR T cells. ICAM1 is upregulated by inflammatory cytokines, reinforces immune-synapse formation, and is elevated in aggressive or dedifferentiated tumors, including those with heterogeneous or low HER2 expression. HER2 CAR/ICCR T cells preserved potent cytotoxicity against HER2-high targets and showed significantly enhanced killing of HER2-low cell lines compared with HER2 CAR T cells alone. ICCR augmented NF-κB activation particularly under low HER2 conditions. Upon repeated stimulation with HER2-negative tumor cells, HER2 CAR/ICCR T cells underwent nearly 10-fold expansion with superior cytotoxicity, whereas HER2 CAR T cells failed to expand. In vivo, both constructs rapidly eliminated HER2-high tumors, but only HER2 CAR/ICCR T cells achieved complete clearance of HER2-low tumors, with delayed kinetics consistent with clonally expanded, tumor-specific T cells. TCR sequencing confirmed substantially greater clonal expansion in HER2 CAR/ICCR T cells across in vivo and in vitro studies. This dual-receptor platform (HMJ01) has supported IND authorization for a first-in-human trial in patients with HER2-positive and HER2-low gastric cancer.