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Updated: Dec 29, 2025
Author Spotlight: Advancements in CAR-T Cell Manufacturing and Gene Therapy Production
Published on: August 18, 2023
A computationally designed chimeric antigen receptor provides a small-molecule safety switch for T-cell therapy
Greta Giordano-Attianese1,2, Pablo Gainza3,4, Elise Gray-Gaillard1,2
1Ludwig Institute for Cancer Research, University of Lausanne (UNIL), Epalinges, Switzerland.
Abstract:
Approaches to increase the activity of chimeric antigen receptor (CAR)-T cells against solid tumors may also increase the risk of toxicity and other side effects. To improve the safety of CAR-T-cell therapy, we computationally designed a chemically disruptable heterodimer (CDH) based on the binding of two human proteins. The CDH self-assembles, can be disrupted by a small-molecule drug and has a high-affinity protein interface with minimal amino acid deviation from wild-type human proteins. We incorporated the CDH into a synthetic heterodimeric CAR, called STOP-CAR, that has an antigen-recognition chain and a CD3ζ- and CD28-containing endodomain signaling chain. We tested STOP-CAR-T cells specific for two antigens in vitro and in vivo and found similar antitumor activity compared to second-generation (2G) CAR-T cells. Timed administration of the small-molecule drug dynamically inactivated the activity of STOP-CAR-T cells. Our work highlights the potential for structure-based design to add controllable elements to synthetic cellular therapies.
Insights
Researchers developed a controllable chimeric antigen receptor (CAR)-T cell therapy using a chemically disruptable heterodimer (CDH). This STOP-CAR system allows for dynamic inactivation of CAR-T cells, enhancing safety in solid tumor treatments.
Area of Science:
- Immunology
- Biotechnology
- Synthetic Biology
Background:
- Chimeric antigen receptor (CAR)-T cell therapy shows promise against solid tumors but faces challenges with toxicity.
- Current CAR-T cell strategies for solid tumors often increase the risk of adverse side effects.
Purpose of the Study:
- To develop a safer and controllable CAR-T cell therapy for solid tumors.
- To engineer a synthetic CAR system with a tunable on/off switch for enhanced safety.
Main Methods:
- Computationally designed a chemically disruptable heterodimer (CDH) based on protein-protein interactions.
- Incorporated the CDH into a synthetic heterodimeric CAR (STOP-CAR) with antigen recognition and signaling domains.
- Evaluated STOP-CAR-T cell activity and controllability in vitro and in vivo models.
Main Results:
- STOP-CAR-T cells demonstrated comparable antitumor activity to conventional second-generation (2G) CAR-T cells.
- Administration of a small-molecule drug dynamically inactivated STOP-CAR-T cell activity.
- The CDH system allowed for precise control over CAR-T cell function.
Conclusions:
- Structure-based design can introduce controllable elements into synthetic cellular therapies.
- STOP-CAR technology offers a promising strategy to improve the safety profile of CAR-T cell therapy.
- This approach has the potential to mitigate CAR-T cell-related toxicities in solid tumor treatment.
