Abstract：
Engineered T cells expressing chimeric antigen receptor (CAR) exhibit high response rates in B-cell malignancy treatments and possess therapeutic potentials against various diseases. However, the complicated ex vivo production process of CAR-T cells limits their application. Herein, we use virus-mimetic fusogenic nanovesicles (FuNVs) to produce CAR-T cells in vivo via membrane fusion-mediated CAR protein delivery. Briefly, the FuNVs are modified using T-cell fusogen, adapted from measles virus or reovirus fusogens via displaying anti-CD3 single-chain variable fragment. The FuNVs can efficiently fuse with the T-cell membrane in vivo, thereby delivering the loaded anti-CD19 (αCD19) CAR protein onto T-cells to produce αCD19 CAR-T cells. These αCD19 CAR-T cells alone or in combination with anti-OX40 antibodies can treat B-cell lymphoma without inducing cytokine release syndrome. Thus, our strategy provides a novel method for engineering T cells into CAR-T cells in vivo and can further be employed to deliver other therapeutic membrane proteins.
摘要：
表达嵌合抗原受体(CAR)的工程化T细胞在B细胞恶性肿瘤治疗中表现出高应答率,并且具有针对各种疾病的治疗潜力。然而,CAR-T细胞复杂的离体生产过程限制了其应用。在这里，我们使用病毒模拟融合纳米囊泡(FuNVs)通过膜融合介导的CAR蛋白递送在体内产生CAR-T细胞.简而言之，使用T细胞融合剂修饰FuNVs，通过展示抗CD3单链可变片段，由麻疹病毒或呼肠孤病毒融合剂改编。FuNVs可以在体内有效地与T细胞膜融合，从而将负载的抗CD19(αCD19)CAR蛋白递送到T细胞上以产生αCD19CAR-T细胞。这些αCD19CAR-T细胞单独或与抗OX40抗体组合可以治疗B细胞淋巴瘤而不诱导细胞因子释放综合征。因此，我们的策略提供了一种在体内将T细胞改造成CAR-T细胞的新方法,并可进一步用于递送其他治疗性膜蛋白.
