A computationally designed chimeric antigen receptor provides a small-molecule safety switch for T-cell therapy

Area of Science:

• Immunology
• Biotechnology
• Synthetic Biology

Background:

• Chimeric antigen receptor (CAR)-T cell therapy shows promise against solid tumors but faces challenges with toxicity.
• Current CAR-T cell strategies for solid tumors often increase the risk of adverse side effects.

Purpose of the Study:

• To develop a safer and controllable CAR-T cell therapy for solid tumors.
• To engineer a synthetic CAR system with a tunable on/off switch for enhanced safety.

Main Methods:

• Computationally designed a chemically disruptable heterodimer (CDH) based on protein-protein interactions.
• Incorporated the CDH into a synthetic heterodimeric CAR (STOP-CAR) with antigen recognition and signaling domains.
• Evaluated STOP-CAR-T cell activity and controllability in vitro and in vivo models.

Main Results:

• STOP-CAR-T cells demonstrated comparable antitumor activity to conventional second-generation (2G) CAR-T cells.
• Administration of a small-molecule drug dynamically inactivated STOP-CAR-T cell activity.
• The CDH system allowed for precise control over CAR-T cell function.

Conclusions:

• Structure-based design can introduce controllable elements into synthetic cellular therapies.
• STOP-CAR technology offers a promising strategy to improve the safety profile of CAR-T cell therapy.
• This approach has the potential to mitigate CAR-T cell-related toxicities in solid tumor treatment.