细胞因子
过继性细胞移植
细胞疗法
细胞因子释放综合征
免疫学
细胞生物学
医学
T细胞
化学
生物
嵌合抗原受体
免疫系统
干细胞
作者
Meng-Yin Lin,Eunwoo Nam,Ryan M. Shih,Amanda Shafer,Amber Bouren,Melanie Ayala Ceja,Caitlin Harris,Mobina Khericha,Kenny Vo,Minsoo Kim,Chi‐Hong Tseng,Yvonne Y. Chen
摘要
Cytokine release syndrome (CRS) is a frequently observed side effect of chimeric antigen receptor (CAR)-T cell therapy. Here, we report self-regulating T cells that reduce CRS severity by secreting inhibitors of cytokines associated with CRS. With a humanized NSG-SGM3 mouse model, we show reduced CRS-related toxicity in mice treated with CAR-T cells secreting tocilizumab-derived single-chain variable fragment (Toci), yielding a safety profile superior to that of single-dose systemic tocilizumab administration. Unexpectedly, Toci-secreting CD19 CAR-T cells exhibit superior in vivo antitumor efficacy compared with conventional CD19 CAR-T cells. scRNA-seq analysis of immune cells recovered from tumor-bearing humanized mice revealed treatment with Toci-secreting CD19 CAR-T cells enriches for cytotoxic T cells while retaining memory T-cell phenotype, suggesting Toci secretion not only reduces toxicity but also significantly alters the overall T-cell composition. This approach of engineering T cells to self-regulate inflammatory cytokine production is a clinically compatible strategy with the potential to simultaneously enhance safety and efficacy of CAR-T cell therapy for cancer.
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