Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Nat Biotechnol. 2019 Sep;37(9):1049-1058. doi: 10.1038/s41587-019-0192-1. Epub 2019 Jul 22.
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.
嵌合抗原受体 (CAR)-T 细胞疗法治疗实体瘤受到限制，原因是靶抗原表达的异质性和缺乏针对针对单一抗原的 CAR-T 细胞靶向的抗原的肿瘤生长。在这里，我们开发了一种双顺反子构建体，以驱动针对 EGFRvIII 的 CAR 的表达，EGFRvIII 是胶质母细胞瘤特异性肿瘤抗原，以及针对 EGFR 的双特异性 T 细胞衔接器 (BiTE)，EGFR 是胶质母细胞瘤中过表达的抗原，但也在正常组织中表达。CART.BiTE 细胞分泌针对 EGFR 的 BiTE，该 BiTE 可重定向 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 细胞无法完全治疗 EGFRvIII 表达异质性的肿瘤，导致 EGFRvIII 阴性、EGFR 阳性的胶质母细胞瘤生长。然而，CART.BiTE 细胞在胶质母细胞瘤的小鼠模型中消除了异质性肿瘤。BiTE-EGFR 在局部有效，但在颅内递送 CART.BiTE 细胞后未在系统中检测到。与 EGFR 特异性 CAR-T 细胞不同，CART.BiTE 细胞不会导致体内人皮肤移植物的毒性。
