Preclinical Development and a Case Report of a Nanobody-Based CLDN18.2 CAR-T IMC002 with Reduced On-Target Off-Tumor Toxicity

作者：Sicheng Du, Ying Zhang, Ruidong Hao, Lupeng Qiu, Chao Li, Yuting Li, Rongrui Liu, Chuanhua Zhao, Juan Li, Shuzheng Ye, Jun Zhou, Yantao Li, Qiaoyong Yi, Shuangshuang Zhang, Minmin Sun, Tianhang Luo, Jianming Xu · 发表于：Molecular Cancer Therapeutics · 年份：2025 · DOI：10.1158/1535-7163.mct-25-0171 · 被引用次数：3 · 研究领域：CAR-T cell therapy research、Monoclonal and Polyclonal Antibodies Research、Microfluidic and Bio-sensing Technologies

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 developme...