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.
Authors
- Junjie Shen (ORCID: https://orcid.org/0000-0002-1952-9866)
- Weiwei Tian (ORCID: https://orcid.org/0009-0000-3830-1210)
- Shuang Wei (ORCID: https://orcid.org/0000-0001-5322-9667)
- Lei Zhang (ORCID: https://orcid.org/0000-0002-0580-0889)
- Lifang Huang (ORCID: https://orcid.org/0000-0002-3431-1953)
- Jiande Cheng (ORCID: https://orcid.org/0000-0001-7714-3147)
- Qi Mei (ORCID: https://orcid.org/0000-0002-9826-5044)
- Jia Wei (ORCID: https://orcid.org/0000-0002-6435-9368)
- Yicheng Zhang (ORCID: https://orcid.org/0000-0003-4300-0900)
- Zhi Yang (ORCID: https://orcid.org/0000-0002-3974-7297)
- Lei Liang (ORCID: https://orcid.org/0000-0002-5397-0284)
- Jun Chen (ORCID: https://orcid.org/0000-0002-4457-5194)
- Cheng Qian (ORCID: https://orcid.org/0000-0003-1500-9991)
- Shaoli Zhang (ORCID: https://orcid.org/0009-0004-1836-714X)
- Ruiying Wang (ORCID: https://orcid.org/0000-0001-6224-8480)
- Xiansheng Liu (ORCID: https://orcid.org/0000-0002-9598-5054)
- Xingcheng Yang (ORCID: https://orcid.org/0000-0002-9147-4791)
- Ling Zhou (ORCID: https://orcid.org/0000-0001-5010-5159)
- Xuejing Yang (ORCID: https://orcid.org/0000-0002-3448-5099)
- Huijing Feng (ORCID: https://orcid.org/0000-0001-5099-2739)
- Lin Su (ORCID: https://orcid.org/0009-0007-4382-6899)
- Shaolong He (ORCID: https://orcid.org/0009-0009-0496-568X)
- Linling Wang (ORCID: https://orcid.org/0000-0002-8317-4051)
- Jingyi Liu (ORCID: https://orcid.org/0009-0001-5605-6682)
- Jie Zhao (ORCID: https://orcid.org/0009-0008-6210-2359)
- Yuting Gong (ORCID: https://orcid.org/0009-0005-7293-6064)
- Xiaoling Yang (ORCID: https://orcid.org/0009-0003-4737-8457)
- Jun Yu (ORCID: https://orcid.org/0009-0003-7963-0207)
- Jiaqi Guo (ORCID: https://orcid.org/0009-0005-0675-4844)
- Yingzi Zhang (ORCID: https://orcid.org/0009-0007-5050-2817)
- Xueli Bai (ORCID: https://orcid.org/0009-0005-4112-9729)
Institutions
- Shanxi Medical University (CN)
- Shanxi Academy of Medical Sciences (CN)
- Tongji Hospital (CN)
- Chongqing Precision Biotech Co., Ltd. (China) (CN)
- Huazhong University of Science and Technology (CN)
- Jinzhou Medical University (CN)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2026-10-27
- DOI
- https://doi.org/10.1158/2159-8290.cd-26-0104
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China