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Updated: Aug 14, 2026
Production of Human CRISPR-Engineered CAR-T Cells
Published on: March 15, 2021
Regulation of CD19 CAR-T cell activation based on an engineered downstream transcription factor
Duško Lainšček1,2, Anja Golob-Urbanc1, Veronika Mikolič3,4
1Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, Ljubljana 1000, Slovenia.
Abstract:
CAR-T cells present a highly effective therapeutic option for several malignant diseases, based on their ability to recognize the selected tumor surface marker in an MHC-independent manner. This triggers cell activation and cytokine production, resulting in the killing of the cancerous cell presenting markers recognized by the chimeric antigen receptor. CAR-T cells are highly potent serial killers that may cause serious side effects, so their activity needs to be carefully controlled. Here we designed a system to control the proliferation and activation state of CARs based on downstream NFAT transcription factors, whose activity can be regulated via chemically induced heterodimerization systems. Chemical regulators were used to either transiently trigger engineered T cell proliferation or suppress CAR-mediated activation when desired or to enhance activation of CAR-T cells upon engagement of cancer cells, shown also in vivo. Additionally, an efficient sensor to monitor activated CD19 CAR-T cells in vivo was introduced. This implementation in CAR-T cell regulation offers an efficient way for on-demand external control of CAR-T cell activity to improve their safety.
Insights
Researchers developed a novel system to control chimeric antigen receptor T-cell (CAR-T) therapy. This system uses chemical regulators to manage CAR-T cell proliferation and activation, enhancing safety and efficacy for cancer treatment.
Area of Science:
- Immunology
- Biotechnology
- Cancer Therapy
Background:
- Chimeric antigen receptor T-cells (CAR-T) are effective cancer therapeutics targeting tumor surface markers.
- CAR-T cells' potency necessitates careful control to mitigate serious side effects.
- Existing CAR-T therapies lack precise external regulation mechanisms.
Purpose of the Study:
- To design a controllable system for CAR-T cell proliferation and activation.
- To enhance the safety and efficacy of CAR-T cell therapy through external regulation.
- To develop an in vivo monitoring system for CAR-T cell activity.
Main Methods:
- Engineered CAR-T cells with NFAT transcription factor-based regulation systems.
- Utilized chemically induced heterodimerization for controlling T-cell activity.
- Developed an in vivo sensor for monitoring activated CD19 CAR-T cells.
Main Results:
- Demonstrated transient triggering of T-cell proliferation via chemical regulators.
- Showcased suppression or enhancement of CAR-mediated activation on demand.
- Successfully monitored activated CD19 CAR-T cells in vivo.
Conclusions:
- The developed system provides on-demand external control of CAR-T cell activity.
- This regulatory system improves the safety profile of CAR-T cell therapy.
- The findings offer a promising strategy for advanced CAR-T cell therapy applications.
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