The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells.

ABSTRACT: Immunotherapy with chimeric antigen receptor (CAR)-engineered T cells can be effective against advanced malignancies. CAR T cells are "living drugs" that require technologies to enable physicians (and patients) to maintain control over the infused cell product. Here, we demonstrate that the tyrosine kinase inhibitor dasatinib interferes with the lymphocyte-specific protein tyrosine kinase (LCK) and thereby inhibits phosphorylation of CD3ζ and ζ-chain of T cell receptor-associated protein kinase 70 kDa (ZAP70), ablating signaling in CAR constructs containing either CD28_CD3ζ or 4-1BB_CD3ζ activation modules. As a consequence, dasatinib induces a function-off state in CD8⁺ and CD4⁺ CAR T cells that is of immediate onset and can be sustained for several days without affe

SUBMITTER: Mestermann K 

PROVIDER: S-EPMC7523030 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature