Zhang Guangyue, Yin Na, Peng Min
State Key Laboratory of Molecular Oncology, Tsinghua University, Beijing, China.
Institute for Immunology, Tsinghua University, Beijing, China.
Nat Commun. 2025 Aug 29;16(1):8088. doi: 10.1038/s41467-025-63427-w.
The efficacy of biologics, such as peptide and protein drugs, is often limited by their short half-lives in vivo, necessitating repeated infusions to maintain therapeutic effects. Here, we demonstrate that long-lived CAR T cells can be leveraged as a versatile platform for long-term delivery of biologics. Our recent findings show that the depletion of BCOR and ZC3H12A induces GD2 CAR T cells into an immortal-like and functional state, which we have termed GD2T cells. These GD2T cells expanded in immunocompetent mice without the need for chemotherapeutic conditioning and persisted as a polyclonal population, safely and almost indefinitely. In leptin-deficient ob/ob mice, a single infusion of GD2T cells producing leptin effectively and durably corrected leptin deficiency. Furthermore, a single infusion of GD2T cells secreting GLP-1 prevented obesity and diabetes in mice fed on a high-fat diet. The longevity, safety, and adaptability of GD2T cells suggest their potential as a general platform for long-term delivery of biologics, offering durable therapeutic efficacy with a single infusion.
诸如肽类和蛋白质药物等生物制品的疗效常常受到其在体内短半衰期的限制,因此需要反复输注以维持治疗效果。在此,我们证明长寿命的嵌合抗原受体(CAR)T细胞可作为一种通用平台用于生物制品的长期递送。我们最近的研究结果表明,BCOR和ZC3H12A的缺失可诱导GD2 CAR T细胞进入一种永生样且有功能的状态,我们将其称为GD2T细胞。这些GD2T细胞在免疫活性小鼠中无需化疗预处理即可扩增,并作为多克隆群体安全且几乎无限期地持续存在。在瘦素缺乏的ob/ob小鼠中,单次输注产生瘦素的GD2T细胞可有效且持久地纠正瘦素缺乏。此外,单次输注分泌胰高血糖素样肽-1(GLP-1)的GD2T细胞可预防高脂饮食喂养小鼠的肥胖和糖尿病。GD2T细胞的长寿性、安全性和适应性表明它们有潜力作为生物制品长期递送的通用平台,单次输注即可提供持久的治疗效果。
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