Ruxolitinib reduces severe CRS response by suspending CAR-T cell function instead of damaging CAR-T cells

鲁索利替尼 免疫系统 细胞因子 T细胞 免疫学 医学 癌症研究 骨髓 骨髓纤维化
作者
Nan Xu,Xiaofei Yang,Shengli Xue,Jingwen Tan,Minghao Li,Jing Ye,Xiaoyan Lou,Zhou Yu,Liqing Kang,Zhiqiang Yan,Lei Yu,Suning Chen,Yi‐Ting Wang
出处
期刊:Biochemical and Biophysical Research Communications [Elsevier]
卷期号:595: 54-61 被引量:14
标识
DOI:10.1016/j.bbrc.2022.01.070
摘要

The therapeutic effect of CAR-T is often accompanied by sCRS, which is the main obstacle to the promotion of CAR-T therapy. The JAK1/2 inhibitor ruxolitinib has recently been confirmed as clinically effective in maintaining control over sCRS, however, its mechanism remains unclear. In this study, we firstly revealed that ruxolitinib significantly inhibited the proliferation of CAR-T cells without damaging viability, and induced an efficacy-favored differentiation phenotype. Second, ruxolitinib reduced the level of cytokine release not only from CAR-T cells, but also from other cells in the immune system. Third, the cytolytic activity of CAR-T cells was restored once the ruxolitinib was removed; however, the cytokines released from the CAR-T cells maintained an inhibited state to some degree. Finally, ruxolitinib significantly reduced the proliferation rate of CAR-T cells in vivo without affecting the therapeutic efficacy after withdrawal at the appropriate dose. We demonstrated pre-clinically that ruxolitinib interferes with both CAR-T cells and the other immune cells that play an important role in triggering sCRS reactions. This work provides useful and important scientific data for clinicians on the question of whether ruxolitinib has an effect on CAR-T cell function loss causing CAR-T treatment failure when applied in the treatment of sCRS, the answer to which is of great clinical significance.
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