High-performance multiplex drug-gated CAR circuits.

Area of Science:

• Immunology
• Biotechnology
• Oncology

Background:

• Chimeric antigen receptor (CAR) T-cell therapy shows promise for cancer treatment but faces challenges like overactivation and antigen escape.
• Current CAR T-cell systems lack precise regulation and multi-antigen targeting capabilities, hindering their clinical application.
• A need exists for advanced CAR T-cell systems controllable by clinically approved drugs.

Purpose of the Study:

• To develop and characterize a novel inducible CAR T-cell system, VIPER CARs (versatile protease regulatable CARs), offering precise ON and OFF switching.
• To evaluate the safety and efficacy of VIPER CARs using FDA-approved pharmaceutical agents.
• To demonstrate the superiority and orthogonality of VIPER CARs compared to existing drug-gated CAR systems.

Main Methods:

• Engineered VIPER CAR circuits incorporating a viral protease domain for inducible regulation.
• Validated CAR T-cell controllability using FDA-approved antiviral protease inhibitors in mouse models.
• Assessed VIPER CAR performance in xenograft tumor and cytokine release syndrome models.
• Benchmarked VIPER CARs against other drug-gated systems and demonstrated orthogonality in vivo.

Main Results:

• VIPER CARs demonstrated precise ON and OFF switching capabilities regulated by antiviral protease inhibitors.
• The system showed best-in-class performance in controlling CAR T-cell activity in preclinical models.
• Orthogonality was confirmed using VIPER CARs and a separate lenalidomide-regulated CAR system.
• Engineered VIPER CAR circuits combined various CAR technologies for enhanced functionality.

Conclusions:

• VIPER CARs represent a significant advancement in CAR T-cell design, offering robust drug-inducible control.
• This multiplexed, drug-gated system enhances safety and enables sophisticated logic for CAR T-cell therapy.
• VIPER CARs hold potential for improving the therapeutic index and expanding the application of CAR T-cell treatments in oncology.