Hypoxia-inducible CEA-targeted CAR T-cell therapy for relapsed stage IV non-small cell lung cancer
Shuang Wei, Jiaqi Guo, Xueli Bai, Ling Zhou, Qi Mei, Shaolong He, Jie Zhao, Shaoli Zhang, Ruiying Wang, Jiande Cheng, Lin Su, Lei Liang, Lei Zhang, Yuting Gong, Jun Yu, Huijing Feng, Jingyi Liu, Xiaoling Yang, Xuejing Yang, Xingcheng Yang, Lifang Huang, Linling Wang, Jun Chen, Junjie Shen, Yingzi Zhang, Yicheng Zhang, Zhi Yang, Cheng Qian, Weiwei Tian, Xiansheng Liu, Jia WeiAbstract
Mitigating on-target off-tumor toxicity remains a central challenge for chimeric antigen receptor (CAR) T-cell therapy for solid tumors. We developed a hypoxia-inducible CAR-T-cell product targeting carcinoembryonic antigen (CEA) that restricts CAR activation to hypoxic tumor niches via oxygen-dependent expression control. In this first-in-human, phase I trial enrolling heavily pretreated patients with relapsed stage IV non-small cell lung cancer (NSCLC), a single infusion of the investigational product achieved an objective response rate of 47% and a disease control rate of 87%, with a manageable safety profile. Exploratory analyses showed that clinical outcomes were associated with baseline factors. Deep single-cell profiling indicated that the clinical response was associated with the expansion of hypoxia-adapted, tumor-reactive-like CD8+ T cells alongside coordinated functional maturation of natural killer (NK) cells. Collectively, these data provide clinical proof-of-concept for hypoxia-inducible CAR design and inform the rational development of strategies leveraging tumor microenvironmental features in solid tumor cellular immunotherapy.