Back to Search
Start Over
CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity.
- Source :
-
Nature biotechnology [Nat Biotechnol] 2019 Sep; Vol. 37 (9), pp. 1049-1058. Date of Electronic Publication: 2019 Jul 22. - Publication Year :
- 2019
-
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.
- Subjects :
- Animals
Antigens, Neoplasm metabolism
Cell Differentiation
ErbB Receptors
Glioblastoma immunology
Glioblastoma metabolism
Humans
Mice
Neoplasms, Experimental
T-Lymphocytes physiology
Antibodies, Bispecific therapeutic use
Antigens, Neoplasm immunology
Glioblastoma therapy
Receptors, Chimeric Antigen
Subjects
Details
- Language :
- English
- ISSN :
- 1546-1696
- Volume :
- 37
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Nature biotechnology
- Publication Type :
- Academic Journal
- Accession number :
- 31332324
- Full Text :
- https://doi.org/10.1038/s41587-019-0192-1