CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity

被引：429

作者：

Choi, Bryan D. ^{[1
,2
,3
]}

Yu, Xiaoling ^{[1
,2
]}

Castano, Ana P. ^{[1
,2
]}

Bouffard, Amanda A. ^{[1
,2
]}

Schmidts, Andrea ^{[1
,2
]}

Larson, Rebecca C. ^{[1
,2
]}

Bailey, Stefanie R. ^{[1
,2
]}

Boroughs, Angela C. ^{[1
,2
]}

Frigault, Matthew J. ^{[1
,2
,4
]}

Leick, Mark B. ^{[1
,2
]}

Scarfo, Irene ^{[1
,2
]}

Cetrulo, Curtis L. ^{[2
,5
]}

Demehri, Shadmehr ^{[2
,6
]}

Nahed, Brian V. ^{[2
,3
]}

Cahill, Daniel P. ^{[2
,3
]}

Wakimoto, Hiroaki ^{[2
,3
]}

Curry, William T. ^{[2
,3
]}

Carter, Bob S. ^{[2
,3
]}

Maus, Marcela V. ^{[1
,2
,4
]}

机构：

[1] Massachusetts Gen Hosp, Canc Ctr, Cellular Immunotherapy Program, Boston, MA 02114 USA

[2] Harvard Med Sch, Boston, MA 02115 USA

[3] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA

[4] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA

[5] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA

[6] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA

来源：

NATURE BIOTECHNOLOGY | 2019年 / 37卷 / 09期

基金：

美国国家卫生研究院;

关键词：

GROWTH-FACTOR RECEPTOR; GLIOBLASTOMA; EGFR; DELIVERY; RECOGNITION; REGRESSION; DENSITY; VARIANT; MODELS;

D O I：

10.1038/s41587-019-0192-1

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

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.

引用

页码：1049 / +

页数：12

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