Split-design approach enhances the therapeutic efficacy of ligand-based CAR-T cells against multiple B-cell malignancies

Shuhong Li, Licai Shi, Lijun Zhao, Qiaoru Guo, Jun Li, Ze-lin Liu, Zhi Guo and Yu J. Cao ()
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Shuhong Li: Peking University Shenzhen Graduate School
Licai Shi: Peking University Shenzhen Graduate School
Lijun Zhao: Peking University Shenzhen Graduate School
Qiaoru Guo: Peking University Shenzhen Graduate School
Jun Li: Ltd
Ze-lin Liu: Huazhong University of Science and Technology Union Shenzhen Hospital (Nanshan Hospital)
Zhi Guo: Huazhong University of Science and Technology Union Shenzhen Hospital (Nanshan Hospital)
Yu J. Cao: Peking University Shenzhen Graduate School

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract To address immune escape, multi-specific CAR-T-cell strategies use natural ligands that specifically bind multiple receptors on malignant cells. In this context, we propose a split CAR design comprising a universal receptor expressed on T cells and ligand-based switch molecules, which preserves the natural trimeric structure of ligands like APRIL and BAFF. Following optimization of the hinges and switch labeling sites, the split-design CAR-T cells ensure the native conformation of ligands, facilitating the optimal formation of immune synapses between target cancer cells and CAR-T cells. Our CAR-T-cell strategy demonstrates antitumor activities against various B-cell malignancy models in female mice, potentially preventing immune escape following conventional CAR-T-cell therapies in the case of antigen loss or switching. This ligand-based split CAR design introduces an idea for optimizing CAR recognition, enhancing efficacy and potentially improving safety in clinical translation, and may be broadly applicable to cellular therapies based on natural receptors or ligands.

Date: 2024
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DOI: 10.1038/s41467-024-54150-z

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