DROP-CARs: Engineering Reversible, Drug-Controlled CAR T-cell Activity with a Clinically Approved Small Molecule

Area of Science:

• Oncology
• Immunotherapy
• Molecular Biology

Background:

• Chimeric antigen receptor (CAR) T cells show promise for cancer therapy but face challenges in solid tumors due to off-target toxicities.
• A lack of tumor-specific targets limits the safe application of CAR T cells in solid tumors, leading to harmful side effects.

Purpose of the Study:

• To engineer controllable CAR T cells for solid tumors by developing a system responsive to an external small molecule.
• To create a CAR T cell therapy that can be reversibly inactivated to mitigate toxicity and improve safety.

Main Methods:

• Development of a novel CAR T cell construct designed for inactivation by the small molecule venetoclax.
• Demonstration of venetoclax-induced release of the CAR extracellular binding domain to disrupt T cell-tumor cell interactions.
• Assessment of the reversibility of CAR T cell function upon withdrawal of venetoclax.

Main Results:

• Successfully engineered a CAR T cell that is inactivated by venetoclax, a clinically approved Bcl-2 inhibitor.
• Showcased venetoclax-dependent disruption of T cell contact with tumor cells, effectively suppressing cytotoxicity.
• Confirmed the reversibility of CAR T cell function, with activity restored after drug withdrawal.

Conclusions:

• Established a foundation for a clinically translatable, remote-controlled CAR T cell therapy for solid tumors.
• The venetoclax-inducible system offers a promising strategy to manage CAR T cell-mediated toxicity in solid tumor treatment.
• This controllable immunotherapy approach enhances safety and precision in CAR T cell therapy.