Published July 4, 2025
| Version v1
Journal article
A universal chimeric antigen receptor (CAR)–fragment antibody binder (FAB) split system for cancer immunotherapy
Description
Chimeric antigen receptor (CAR) T cell therapy has shown extraordinary results in treating hematological cancer but faces challenges like antigen loss, toxicity, and complex manufacturing. Universal and modular CAR constructs offer improved flexibility, safety, and cost-effectiveness over conventional CAR constructs. We present a CAR–fragment antibody binder (Fab) platform on the basis of an engineered protein G variant (GA1) and Fab scaffolds. Expression of GA1CAR on human CD8+ T cells leads to antigen recognition and T cell effector function that can be modulated according to the affinity of the CAR for the Fab and of the Fab for the target. GA1CAR T cells can recognize multiple Fab-antigen pairs on breast and ovarian cancer cell lines. Adoptively transferred GA1CAR T cells control tumors in breast cancer xenograft models, and their targeting can be quickly redirected using different Fabs. This versatile "plug-and-play" CAR T platform has potential for application in personalized therapy, preventing antigen loss variant escape, decreasing toxicity, and increasing access.
Data availability
All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.Additional details
Identifiers
- DOI
- 10.1126/sciadv.adv4937
- Other
- oai:uchicago.tind.io:16203
Funding
- National Cancer Institute
- R21 CA267607-01A1
- Chicago Biomedical Consortium
- Ludwig Foundation for Cancer Research
- Animal Studies Core
- SCR_021806
- Functional Genomics Core
- SCR_019196
- The Center for Research Informatics Core
- SCR_022937
- Flow Cytometry Core
- SCR_017760