Preclinical development and a case report of a nanobody-based CLDN18.2 CAR-T IMC002 with reduced on-target off-tumor toxicity

Abstract 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 (OTOT) 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 cancer 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 cancer with reduced OTOT toxicity. In vivo pharmacological studies revealed that peak concentrations of CAR gene DNA copies in total DNA in the tumor and lung tissues occurred on seven days after administration, while the peak in stomach tissues was observed an additional seven days later. Toxicity studies showed no obvious body weight loss induced by IMC002. The highest non-severely toxic dose was 5×108 CAR-T cells/kg. In the clinical case report, we present a case with unresectable advanced gastric cancer achieved pathological complete response 10 months after IMC002 infusion and no signs of recurrence were indicated in subsequent clinical and radiological follow-ups. IMC002 shows effectiveness and safety in CLDN18.2-positive gastric and pancreatic cancer and its favorable profiles support further clinical development.