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Systematic Engineering of TROP2-Targeted CAR T-Cell Therapy Overcomes Resistance Pathways in Solid Tumors
Elliott J Brea1, Simon Baldacci1, Neil Savage1
1Dana-Farber Cancer Institute, Boston, Massachusetts.
Abstract:
Antibody-based therapies have revolutionized cancer treatment but have several limitations. These include downregulation of the target antigen, mutation of the target epitope, and, in the case of antibody-drug conjugates (ADC), resistance to the chemotherapy warhead. As TROP2-targeted therapy with ADCs yields responses in TROP2+ solid tumors, but the responses lack the durability observed with other immunotherapy-based approaches, we developed TROP2-targeting chimeric antigen receptor (CAR) T cells as an alternative. The TROP2-directed CAR T cells showed high potency against multiple solid tumor models. Moreover, TROP2-directed CAR T-cell therapy preserved high potency in models of ADC resistance and could be further engineered to prevent cell therapy resistance. This was achieved by leveraging fully human single-domain (VH-only) binder discovery to rationally engineer dual epitope binding-based (biparatopic) CARs. This work highlights the potency of CAR T-cell therapies and how rational engineering leveraging dual-VH targeting domains can overcome resistance pathways to current therapies. In future work, the CAR engineering approaches presented here can serve as a platform to be partnered with other strategies to address the suppressive tumor microenvironment.
Insights
Chimeric antigen receptor (CAR) T cells targeting TROP2 offer a potent alternative to antibody-drug conjugates for solid tumors. Rational engineering of these CAR T cells overcomes resistance, enhancing durability and providing a platform for future cancer therapies.
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.
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