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Tripterygium glycosides as a potential treatment for CAR-T induced cytokine release syndrome: implication of monocyte depletion

By Zuqiong Xu, Fang Tian, Biqing Chen, Xiangtu Kong, Xingbin Dai, Jiang Cao, Pengjun Jiang, Jianxin Tan, Lu Lu, Xiachang Wang, Qi Lv, Di Kang, Miao Xu, Yingying Hu, Aiping Yang, Qian Wang, Zhong-Fa Yang, Xuemei Sun, Leyuan Ma, Lihong Hu, Xuejun Zhu

Posted 27 Nov 2020
medRxiv DOI: 10.1101/2020.11.22.20232801

Background Cytokine release syndrome (CRS) is a potentially life-threatening complication of chimeric antigen receptor T (CAR-T) cell therapy. Recent studies indicated critical roles of macrophages and monocytes in CAR-T induced CRS. Here, we report rapid dissipation of CAR-T induced CRS in two patients after receiving Tripterygium glycosides (TG). Effects of triptolide, the major active component of TG, on macrophages and monocytes were examined in animal models. Methods Two patients with CRS after CAR-T cell therapy (for hematological malignancy) received TG (50 mg, p.o.). Flow cytometry analysis and single cell RNA sequencing (scRNAseq) were conducted to examine the effects of TG on immune cells. Potential effects of triptolide were also examined ex vivo using patient-derived monocytes, as well as in mice. Findings Rapid alleviation of fever and cytokine storm was observed within 72 hours after TG treatment. Blood concentration of triptolide ranged from 21 to 154 ng/mL during treatment. Flow cytometry and scRNAseq showed selective depletion of monocytes with minimal impact on CAR-T cells in both patients. In ex vivo experiments with patient-derived monocytes, triptolide dramatically inhibited the synthesis of pro-inflammatory cytokines (e.g., IL-6, IL-10, and IP-10). Triptolide also rapidly and selectively depleted peritoneal concanavalin A activated macrophages and monocytes in mice. Interpretation TG could be a promising treatment for CAR-T induced CRS, as well as other diseases with similar mechanisms, e.g., hemophagocytic lymphohistiocytosis and COVID-19. Our preliminary findings require further verification with properly designed clinical trials.

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