CELL INTELLIGENCE · 肿瘤细胞治疗研究

Claudin18.2 (CLDN18.2)-targeted chimeric antigen receptor T (CAR-T) cell therapy has shown promising antitumor activity in gastrointestinal cancers. However, limited persistence in solid tumors and on-target off-tumor toxicity remain significant challenges. Here, we report on the preclinical development of a nanobody-based CLDN18.2-targeted CAR-T (IMC002) with effectiveness and safety in CLDN18.2-positive gastric and pancreatic cancers and present an efficacious clinical case. IMC002 exhibited robust antitumor activity and tolerability in multiple CLDN18.2-positive cell-derived xenograft and patient-derived xenograft models of gastric and pancreatic cancers with reduced on-target off-tumor toxicity. In vivo pharmacologic studies revealed that peak concentrations of CAR gene DNA copies in total DNA in the tumor and lung tissues occurred on 7 days after administration, whereas the peak in stomach tissues was observed an additional 7 days later. Toxicity studies showed no obvious body weight loss induced by IMC002. The highest nonseverely toxic dose was 5 108 CAR-T cells/kg. In the clinical case report, we present a case with unresectable advanced gastric cancer that achieved pathologic complete response 10 months after IMC002 infusion, and no signs of recurrence were indicated in subsequent clinical and radiologic follow-ups. IMC002 shows effectiveness and safety in CLDN18.2-positive gastric and pancreatic cancers, and its favorable profiles support further clinical development.