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Updated: Jun 7, 2025
A Nonviral Approach to Generate Transient Chimeric Antigen Receptor T Cells Using mRNA for Cancer Immunotherapy
Published on: February 21, 2025
Split-design approach enhances the therapeutic efficacy of ligand-based CAR-T cells against multiple B-cell
Shuhong Li1, Licai Shi1, Lijun Zhao1
1State Key Laboratory of Chemical Oncogenomics, Shenzhen Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, China.
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.
Insights
This study introduces a novel split chimeric antigen receptor (CAR)-T-cell strategy using natural ligands to prevent immune escape in cancer therapy. This approach enhances CAR-T-cell efficacy and safety for B-cell malignancies.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Cancer immune escape is a significant challenge in CAR-T-cell therapy.
- Multi-specific CAR-T-cell strategies aim to overcome this by targeting multiple receptors on cancer cells.
- Natural ligands like APRIL and BAFF offer potential for specific targeting.
Purpose of the Study:
- To develop a split CAR design that preserves the natural conformation of ligands.
- To enhance CAR-T-cell recognition, efficacy, and safety.
- To investigate antitumor activity against B-cell malignancies.
Main Methods:
- Proposed a split CAR design with a universal receptor and ligand-based switch molecules.
- Optimized hinge regions and switch labeling sites.
- Evaluated CAR-T-cell strategy in B-cell malignancy models in female mice.
Main Results:
- The split CAR design maintained the native trimeric structure of ligands (APRIL, BAFF).
- Facilitated optimal immune synapse formation between CAR-T cells and cancer cells.
- Demonstrated significant antitumor activities against various B-cell malignancy models.
Conclusions:
- The ligand-based split CAR design offers a novel approach to optimize CAR recognition and enhance therapeutic efficacy.
- This strategy shows potential for preventing immune escape due to antigen loss or switching.
- The design may broadly apply to cellular therapies utilizing natural receptors or ligands, improving clinical translation and safety.
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