Reversible ON- and OFF-switch chimeric antigen receptors controlled by lenalidomide

Area of Science:

• Biotechnology
• Immunotherapy
• Molecular Biology

Background:

• Cell-based therapies, like Chimeric Antigen Receptor (CAR) T cells, show promise for treating cancer and other diseases.
• CAR T cells act as autonomous

Purpose of the Study:

• To develop precise ON and OFF switches for controlling CAR T cell activity.
• To engineer CAR T cells with lenalidomide-inducible control systems for enhanced safety and efficacy.

Main Methods:

• Systematic screening for "super-degron" tags sensitive to lenalidomide-induced degradation.
• Engineering lenalidomide-inducible dimerization systems and split CARs for ON-switch functionality.
• Developing OFF-switch degradable CARs using identified degron tags.

Main Results:

• Subtherapeutic lenalidomide concentrations effectively controlled ON- and OFF-switch CAR T cell functions.
• ON-switch split CARs demonstrated lenalidomide-dependent antitumor activity in vivo.
• OFF-switch degradable CARs were depleted upon drug treatment, reducing cytokine production while maintaining efficacy.

Conclusions:

• Lenalidomide-gated switches provide rapid, reversible control over CAR T cell transgene function.
• These systems are clinically suitable for diverse gene- and cell-based therapies.
• The developed switches enhance the safety and therapeutic potential of living drugs.