Recently, a pharmaceutical research team led by Prof. LIU Qingsong at the Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, in collaboration with Tongji University, identified a natural compound, Timosaponin AIII (TAIII), that selectively eliminates CAR-T regulatory T cells.
The study was published in Nature Communications.
CAR-T cell therapy works well in blood cancers, but many patients still become resistant. A key reason is the presence of CAR-T regulatory T cells (CAR-Tregs), which weaken immune responses. Therefore, selectively targeting CAR-Tregs while preserving CAR-T activity remains a major challenge.
In this study, the researchers screened over 3,000 small molecules using a high-throughput platform. TAIII, a natural product derived from Anemarrhena asphodeloides, was identified as an effective regulator of T cell suppression. Further studies showed that TAIII blocks the adenosine A2A receptor, a key immune checkpoint, thereby reducing suppressive T cell activity.
In cell experiments, TAIII restored CAR-T function and enhanced its killing ability. In lymphoma models, combining TAIII with CAR-T therapy significantly inhibited tumor growth, reduced relapse, and extended survival. It also improved the effectiveness of patient-derived CAR-T cells.
In solid tumor models, TAIII reduced suppressive immune cells and increased cancer-killing T cells, making tumors more responsive to immunotherapy. It also showed strong synergy with CAR-T therapy and anti-PD-1 treatment.
Compared with an A2A receptor inhibitor currently in clinical trials, TAIII achieved similar anti-tumor effects at lower doses and with less frequent administration, suggesting good clinical potential.
"Our study suggests that TAIII is a promising natural immunomodulator that can improve CAR-T therapy by reducing immune suppression," said Associate Professor QI Ziping, a member of the team.
Timosaponin AIII (TAIII) enhances the anti-tumor efficacy of CAR-T cells in vitro and in vivo. (Image by HOU Mingqi)
