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Updated: Jun 7, 2025
Author Spotlight: Enhancing CAR-T Cell Function in Syngeneic Tumor Models
Published on: February 2, 2024
Improved safety of chimeric antigen receptor T cells indirectly targeting antigens via switchable adapters
Hyung Bae Park1,2,3, Ki Hyun Kim1,3, Ju Hwan Kim4
1Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Republic of Korea.
Abstract:
Chimeric antigen receptor T (CAR-T) cells show remarkable efficacy for some hematological malignancies. However, CAR targets that are expressed at high level and selective to tumors are scarce. Several strategies have been proposed to tackle the on-target off-tumor toxicity of CAR-T cells that arise from suboptimal selectivity, but these are complicated, with many involving dual gene expression for specificity. In this study, we show that switchable CAR-T cells with a tumor targeting adaptor can mitigate on-target off-tumor toxicity against a low selectivity tumor antigen that cannot be targeted by conventional CAR-T cells, such as CD40. Our system is composed of anti-cotinine murine CAR-T cells and cotinine-labeled anti-CD40 single chain variable fragments (scFv), with which we show selective tumor killing while sparing CD40-expressing normal cells including macrophages in a mouse model of lymphoma. Simple replacement of the tumor-targeting adaptor with a suicidal drug-conjugated tag may further enhance safety by enabling permanent in vivo depletion of the switchable CAR-T cells when necessary. In summary, our switchable CAR system can control CAR-T cell toxicity while maintaining therapeutic efficacy, thereby expanding the range of CAR targets.
Insights
Switchable CAR-T cells offer a novel solution to target tumors with low selectivity antigens like CD40. This adaptable system enhances safety by controlling T-cell toxicity, expanding potential CAR targets for cancer therapy.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Chimeric antigen receptor T (CAR-T) cell therapy is effective against hematological malignancies.
- Limited tumor-specific targets and on-target, off-tumor toxicity hinder CAR-T cell application.
- Current strategies to improve CAR-T cell selectivity are often complex.
Purpose of the Study:
- To develop a switchable CAR-T cell system for targeting antigens with low tumor selectivity, such as CD40.
- To mitigate on-target, off-tumor toxicity associated with conventional CAR-T cells.
- To expand the range of treatable cancers using CAR-T cell therapy.
Main Methods:
- Engineered anti-cotinine CAR-T cells and cotinine-labeled anti-CD40 single-chain variable fragments (scFv) were developed.
- The system's efficacy and selectivity were evaluated in a mouse model of lymphoma.
- Potential safety enhancements using a suicidal drug-conjugated tag were explored.
Main Results:
- The switchable CAR-T cell system demonstrated selective tumor killing against CD40-expressing lymphoma.
- Normal CD40-expressing cells, including macrophages, were spared, indicating reduced off-tumor toxicity.
- The system offers a modular approach for controlling CAR-T cell activity.
Conclusions:
- Switchable CAR-T cells with tumor-targeting adaptors can overcome limitations of conventional CAR-T cells for low-selectivity antigens.
- This adaptable system enhances safety and expands the therapeutic potential of CAR-T cell therapy.
- Future strategies could incorporate inducible depletion mechanisms for enhanced safety.
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