Systematic Engineering of TROP2-Targeted CAR T-Cell Therapy Overcomes Resistance Pathways in Solid Tumors

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Antibody-based cancer therapies face limitations like antigen downregulation and drug resistance.
• TROP2-targeted antibody-drug conjugates (ADCs) show efficacy but lack durable responses in solid tumors.

Purpose of the Study:

• To develop TROP2-targeting chimeric antigen receptor (CAR) T cells as a durable alternative to ADCs.
• To engineer CAR T cells to overcome resistance mechanisms observed with current therapies.

Main Methods:

• Development of TROP2-directed CAR T cells.
• Testing CAR T-cell potency against solid tumor models, including those resistant to ADCs.
• Engineering biparatopic CARs using fully human single-domain binders to enhance targeting and overcome resistance.

Main Results:

• TROP2-directed CAR T cells demonstrated high potency against various solid tumor models.
• CAR T-cell therapy maintained potency in models resistant to antibody-drug conjugates.
• Engineered biparatopic CARs successfully prevented cell therapy resistance.

Conclusions:

• TROP2-targeting CAR T cells represent a potent and potentially more durable immunotherapy for TROP2+ solid tumors.
• Rational engineering of CARs, particularly biparatopic designs, can overcome resistance pathways.
• This CAR engineering approach provides a platform for developing next-generation cancer cell therapies.