期刊
NATURE BIOTECHNOLOGY
卷 37, 期 9, 页码 1049-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41587-019-0192-1
关键词
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资金
- National Institutes of Health [R25NS065743]
- Neurosurgery Research & Education Foundation
- B* Cured Research Fellowship Grant
- Society for Immunotherapy of Cancer-AstraZeneca Postdoctoral Cancer Immunotherapy in Combination Therapies Clinical Fellowship Award
- Jenny Fund
- Damon Runyon-Rachleff Innovation Award
- Stand Up to Cancer
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.
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