研究揭示CAR-T细胞绕过抗原逃逸的机制
美国马萨诸塞州综合医院和哈佛医学院Marcela V. Maus研究团队发现，分泌双特异性T细胞衔接体（BiTE）的嵌合抗原受体（CAR）-T细胞，可以绕过抗原逃逸而无明显毒性的机制。相关论文于2019年9月发表在《自然—生物技术》上。
他们使用双顺反子构建体以驱动EGFRvIII特异性CAR的表达，EGFRvIII是一种胶质母细胞瘤特异性肿瘤抗原，以及针对EGFR的（BiTE）。EGFR是一种在胶质母细胞瘤中频繁过表达但在正常组织中也表达的抗原。CART.BiTE细胞分泌EGFR特异性BiTE，其重定向CAR-T细胞并募集未转导的旁观者T细胞对抗野生型EGFR。EGFRvIII特异性CAR-T细胞不能完全治疗具有异源EGFRvIII表达的肿瘤，导致EGFRvIII阴性、EGFR阳性胶质母细胞瘤的生长。然而，CART.BiTE细胞消除了胶质母细胞瘤小鼠模型中的异源肿瘤。 BiTE-EGFR局部有效但在颅内递送CART.BiTE细胞后未检测到系统效应。与EGFR特异性CAR-T细胞不同，CART.BiTE细胞在体内不会对人皮肤移植产生毒性。
研究人员介绍，由于异源靶抗原表达和缺乏针对单个抗原的CAR-T细胞靶向的抗原肿瘤的生长，CAR-T细胞疗法用于实体瘤受到限制。
附：英文原文
Title: CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity
Author: Bryan D. Choi, Xiaoling Yu, Ana P. Castano, Amanda A. Bouffard, Andrea Schmidts, Rebecca C. Larson, Stefanie R. Bailey, Angela C. Boroughs, Matthew J. Frigault, Mark B. Leick, Irene Scarf, Curtis L. Cetrulo, Shadmehr Demehri, Brian V. Nahed, Daniel P. Cahill, Hiroaki Wakimoto, William T. Curry, Bob S. Carter, Marcela V. Maus
Issue&Volume:Volume 37 Issue 9
Abstract: Chimeric antigen receptor (CAR)-T-cell therapy for solid tumors is limited due to heterogeneous target antigen expression and outgrowth of tumors lacking the antigen targeted by CAR-T cells directed against single antigens. Here, we developed a bicistronic construct to drive expression of a CAR specific for EGFRvIII, a glioblastoma-specific tumor antigen, and a bispecific T-cell engager (BiTE) against EGFR, an antigen frequently overexpressed in glioblastoma but also expressed in normal tissues. CART.BiTE cells secreted EGFR-specific BiTEs that redirect CAR-T cells and recruit untransduced bystander T cells against wild-type EGFR. EGFRvIII-specific CAR-T cells were unable to completely treat tumors with heterogenous EGFRvIII expression, leading to outgrowth of EGFRvIII-negative, EGFR-positive glioblastoma. However, CART.BiTE cells eliminated heterogenous tumors in mouse models of glioblastoma. BiTE-EGFR was locally effective but was not detected systemically after intracranial delivery of CART.BiTE cells. Unlike EGFR-specific CAR-T cells, CART.BiTE cells did not result in toxicity against human skin grafts in vivo.
DOI: 10.1038/s41587-019-0192-1
Source: https://www.nature.com/articles/s41587-019-0192-1
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