CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity
CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity
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DOI：
10.1038/s41587-019-0192-1
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发表时间：
2019-09-01
影响因子：
46.9
通讯作者：
Maus, Marcela V.
中科院分区：
文献类型：
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作者：
Choi, Bryan D.;Yu, Xiaoling;Maus, Marcela V.
嵌合抗原受体（CAR）-T细胞疗法在实体瘤中的应用受到限制，这是因为靶抗原表达的异质性以及缺乏CAR - T细胞所针对的单一抗原的肿瘤的生长。在此，我们开发了一种双顺反子构建体，以驱动对表皮生长因子受体变异体III（EGFRvIII，一种胶质母细胞瘤特异性肿瘤抗原）具有特异性的CAR以及一种针对表皮生长因子受体（EGFR，一种在胶质母细胞瘤中经常过度表达但也在正常组织中表达的抗原）的双特异性T细胞衔接器（BiTE）的表达。CAR - BiTE细胞分泌针对EGFR的特异性BiTE，其可重定向CAR - T细胞并招募未转导的旁观者T细胞来对抗野生型EGFR。针对EGFRvIII的特异性CAR - T细胞无法完全治疗具有异质性EGFRvIII表达的肿瘤，从而导致EGFRvIII阴性、EGFR阳性的胶质母细胞瘤生长。然而，CAR - BiTE细胞在胶质母细胞瘤小鼠模型中消除了异质性肿瘤。BiTE - EGFR在局部有效，但在颅内给予CAR - BiTE细胞后在全身未检测到。与针对EGFR的特异性CAR - T细胞不同，CAR - BiTE细胞在体内不会对人皮移植产生毒性。
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.