Repurposing a Small Molecule Plant Hormone as a Tunable ON-Switch for CAR-T Cell Immunotherapy

Area of Science:

• Immunology
• Molecular Biology
• Biotechnology

Background:

• Precise control of chimeric antigen receptor (CAR)-T cell activity is crucial for balancing therapeutic efficacy and minimizing adverse effects.
• Existing switch-controlled CAR-T systems face challenges including inaccurate activation, immunogenicity, and off-target effects.

Purpose of the Study:

• To develop a novel inducible ON-switch CAR design using plant hormone signaling components for controllable T cell activation.
• To engineer a plant hormone-based orthogonal system to overcome limitations of current CAR-T switch technologies.

Main Methods:

• Engineered a CAR system integrating the plant auxin receptor AFB1 and its co-receptor IAA7.
• Utilized plant hormone auxins as ligands to trigger CAR-T cell activation in a dose-dependent and reversible manner.
• Evaluated cytotoxicity against B-cell lymphoma in vitro and in vivo using engineered auxCAR-T cells.

Main Results:

• Demonstrated rapid, reversible, and dose-dependent T cell activation mediated by auxins.
• Achieved potent anti-lymphoma cytotoxicity in vitro and in vivo with auxCAR-T cells.
• Observed that synthetic auxin analogs maintained a favorable memory phenotype and reduced functional exhaustion in CAR-T cells, improving therapeutic outcomes.

Conclusions:

• The novel plant hormone-based inducible ON-switch CAR system offers precise control over T cell activity.
• This approach overcomes key limitations of existing CAR-T switch systems, advancing the development of precision immunotherapy.
• The auxCAR-T system holds significant promise for safer and more effective cancer treatment strategies.