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

Area of Science:

• Immunology
• Pharmacology
• Oncology

Background:

• Chimeric antigen receptor (CAR) T cell immunotherapy shows promise for advanced cancers.
• Controlling CAR T cell activity is crucial for patient safety and therapeutic efficacy.
• Existing methods for CAR T cell control are limited.

Purpose of the Study:

• To identify a pharmacologic agent capable of reversibly controlling CAR T cell function.
• To investigate the mechanism by which dasatinib inhibits CAR T cell activity.
• To evaluate dasatinib's potential in managing CAR T cell-related toxicities like cytokine release syndrome (CRS).

Main Methods:

• Investigated the effect of dasatinib on CAR T cell signaling pathways, including LCK, CD3ζ, and ZAP70 phosphorylation.
• Assessed dasatinib's impact on CAR T cell functions such as cytotoxicity, cytokine production, and proliferation in vitro and in vivo.
• Evaluated the reversibility of dasatinib's inhibitory effects upon drug discontinuation.
• Tested dasatinib's efficacy in a mouse model of cytokine release syndrome (CRS).

Main Results:

• Dasatinib inhibits LCK, leading to suppressed CD3ζ and ZAP70 phosphorylation and abrogated signaling in CAR T cells.
• Dasatinib induces a reversible, immediate, and sustained function-off state in CAR T cells without affecting viability.
• Treatment with dasatinib effectively halts CAR T cell cytolytic activity, cytokine release, and proliferation.
• Dasatinib administration protected mice from lethal cytokine release syndrome (CRS) in a preclinical model.

Conclusions:

• Dasatinib serves as a broadly applicable pharmacologic on/off switch for CAR T cells.
• This controllable inhibition allows for real-time steering of CAR T cell activity in "function-on-off-on" sequences.
• Dasatinib offers a potential strategy for managing severe toxicities associated with CAR T cell therapy, such as CRS.