Hypoxia-inducible CEA-targeted CAR T-cell therapy for relapsed stage IV non-small cell lung cancer

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.