Engineering AvidCARs for combinatorial antigen recognition and reversible control of CAR function

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Chimeric antigen receptor (CAR)-T cell therapy shows promise for B cell malignancies but faces challenges in solid tumors due to non-specific antigens and limited T cell control.
• Current CAR-T cell therapies often lack tumor specificity and precise activity regulation, hindering their application against solid tumors.

Purpose of the Study:

• To develop an advanced CAR-T cell platform, termed AvidCAR, with inducible and logic control functions for improved targeting of solid tumors.
• To engineer CARs with reduced antigen-binding affinities and controlled dimerization to enhance avidity-dependent tumor recognition.

Main Methods:

• Designed an improved CAR structure enabling controlled CAR dimerization.
• Reduced antigen-binding affinities to necessitate bivalent interactions (avidity) for T cell activation.
• Developed ON-switch CARs regulated by a clinical drug and AND-gate CARs recognizing dual antigens.

Main Results:

• Demonstrated the versatility of the AvidCAR platform through the creation of drug-inducible and logic-gated CARs.
• Showcased the potential for enhanced tumor specificity through avidity-based antigen recognition.
• Established a novel approach for controlling CAR-T cell activity.

Conclusions:

• The AvidCAR platform offers a versatile strategy for developing controllable CAR-T cell therapies.
• AvidCAR is expected to significantly improve tumor specificity and safety in CAR-T cell treatments for solid tumors.
• This platform holds promise for advancing the clinical application of CAR-T cell therapies beyond hematological cancers.