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Updated: Jun 9, 2025
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A Real-time Potency Assay for Chimeric Antigen Receptor T Cells Targeting Solid and Hematological Cancer Cells
Published on: November 12, 2019
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Dual ON/OFF-switch chimeric antigen receptor controlled by two clinically approved drugs.
Greta Maria Paola Giordano Attianese1, Sailan Shui2,3, Elisabetta Cribioli1
1Ludwig Institute for Cancer Research Lausanne, Department of Oncology, University of Lausanne and Lausanne University Hospital, Lausanne 1011, Switzerland.
Summary
This study introduces novel inducible chimeric antigen receptors (iON-CARs and iONØ-CARs) that allow remote control of T cell activity using small molecules like venetoclax and lenalidomide, enhancing safety and persistence.
Area of Science:
- Immunology
- Cellular Therapy
- Molecular Engineering
Background:
- Chimeric antigen receptors (CARs) enhance T cell-mediated cancer therapy.
- Controlling CAR T cell activity remotely improves safety and efficacy.
- Split CAR designs separate antigen binding from T cell activation.
Purpose of the Study:
- To develop novel inducible CARs (iON-CAR and iONØ-CAR) for small molecule-controlled T cell activity.
- To evaluate the dose-dependent response and reversibility of iON-CAR T cells.
- To create an all-in-one ON/OFF-switch CAR (iONØ-CAR) with tunable activity.
Main Methods:
- Engineered iON-CARs using the anti-apoptotic BCL2 protein, associating with venetoclax.
- Assessed iON-CAR T cell activity in vitro and in vivo with venetoclax and navitoclax.
- Developed iONØ-CAR by fusing a degron sequence for lenalidomide-induced downregulation.
Main Results:
- iON-CAR T cells showed dose-dependent responses to target cells with venetoclax or navitoclax.
- Venetoclax withdrawal led to loss of iON-CAR T cell activity within 48 hours.
- iONØ-CAR T cells were functionally inactivated within 24 hours of lenalidomide treatment.
Conclusions:
- Remote-controlled CAR designs offer improved safety and reduced toxicity.
- Periodic T cell 'rest' via iON and iONØ-CARs may alleviate exhaustion and enhance persistence.
- These inducible CAR systems hold promise for improved long-term tumor control.
