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Nat Biotechnol. 2019 Sep;37(9):1049-1058. doi: 10.1038/s41587-019-0192-1. Epub 2019 Jul 22.

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

Author information

1
Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
2
Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
3
Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
4
Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
5
Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
6
Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. mvmaus@mgh.harvard.edu.
7
Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. mvmaus@mgh.harvard.edu.

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.

PMID:
31332324
DOI:
10.1038/s41587-019-0192-1
[Indexed for MEDLINE]

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