Drug-controlled CAR T cells through the regulation of cell-cell interactions

Area of Science:

• Immunotherapy
• Synthetic Biology
• Molecular Engineering

Background:

• Chimeric antigen receptor (CAR) T cell therapy faces challenges including on-target, off-tumor toxicities and T cell exhaustion due to persistent antigen exposure.
• Existing CAR designs with small-molecule switches are limited by the availability of suitable, non-immunogenic protein components responsive to safe, clinically approved drugs.

Purpose of the Study:

• To develop novel drug-regulated CAR T-cell systems (DROP-CARs) for improved safety and therapeutic control.
• To engineer CARs that utilize small molecules to modulate T cell activity and tumor targeting.

Main Methods:

• Rational design and library-based optimization of a human protein-protein interaction (PPI) to create venetoclax-controlled "drug-regulated off-switch PPI" (DROP)-CARs.
• Development of dual-DROP-CARs responsive to different small molecules and logic-gated synthetic receptors for STAT3 signaling.
• In vitro and in vivo functional assessment of engineered CAR T cells.

Main Results:

• DROP-CARs enable dose-dependent release of the tumor-targeting scFv, reducing T cell binding to tumor cells.
• Proof-of-concept for dual-DROP-CARs and logic-gated synthetic receptors was successfully demonstrated.
• Engineered DROP-CAR T cells exhibited functional activity in vitro and in vivo.

Conclusions:

• DROP-CAR technology provides a promising strategy for enhancing the safety and efficacy of CAR T cell therapy.
• This approach allows for precise control over T cell activity using clinically approved small molecules.
• The developed system holds potential for future clinical applications in cancer immunotherapy.