嵌合抗原受体
癌症研究
肿瘤微环境
免疫检查点
自分泌信号
旁分泌信号
体内
免疫系统
免疫疗法
化学
免疫学
医学
受体
生物
肿瘤细胞
内科学
生物技术
作者
Sarwish Rafiq,Oladapo Yeku,Hollie J. Jackson,Terence J. Purdon,Dayenne G. van Leeuwen,Dylan J. Drakes,Mei Song,Matthew M. Miele,Zhuoning Li,Pei Wang,Yan Su,Jingyi Xiang,Xiaojing Ma,Venkatraman Seshan,Ronald C. Hendrickson,Cheng Liu,Renier J. Brentjens
摘要
The efficacy of chimeric antigen receptor (CAR) T cell therapy against poorly responding tumors can be enhanced by administering the cells in combination with immune checkpoint blockade inhibitors. Alternatively, the CAR construct has been engineered to coexpress factors that boost CAR-T cell function in the tumor microenvironment. We modified CAR-T cells to secrete PD-1-blocking single-chain variable fragments (scFv). These scFv-secreting CAR-T cells acted in both a paracrine and autocrine manner to improve the anti-tumor activity of CAR-T cells and bystander tumor-specific T cells in clinically relevant syngeneic and xenogeneic mouse models of PD-L1+ hematologic and solid tumors. The efficacy was similar to or better than that achieved by combination therapy with CAR-T cells and a checkpoint inhibitor. This approach may improve safety, as the secreted scFvs remained localized to the tumor, protecting CAR-T cells from PD-1 inhibition, which could potentially avoid toxicities associated with systemic checkpoint inhibition.
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