Regulation of CD19 CAR-T cell activation based on an engineered downstream transcription factor
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 presenti...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-06-01
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| Series: | Molecular Therapy: Oncolytics |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S237277052300030X |
| _version_ | 1797828115534184448 |
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| author | Duško Lainšček Anja Golob-Urbanc Veronika Mikolič Jelica Pantović-Žalig Špela Malenšek Roman Jerala |
| author_facet | Duško Lainšček Anja Golob-Urbanc Veronika Mikolič Jelica Pantović-Žalig Špela Malenšek Roman Jerala |
| author_sort | Duško Lainšček |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T12:59:43Z |
| format | Article |
| id | doaj.art-58eb7d12412e46ef89b62bc6107018b9 |
| institution | Directory Open Access Journal |
| issn | 2372-7705 |
| language | English |
| last_indexed | 2024-04-09T12:59:43Z |
| publishDate | 2023-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncolytics |
| spelling | doaj.art-58eb7d12412e46ef89b62bc6107018b92023-05-13T04:25:18ZengElsevierMolecular Therapy: Oncolytics2372-77052023-06-01297790Regulation of CD19 CAR-T cell activation based on an engineered downstream transcription factorDuško Lainšček0Anja Golob-Urbanc1Veronika Mikolič2Jelica Pantović-Žalig3Špela Malenšek4Roman Jerala5Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, Ljubljana 1000, Slovenia; EN-FIST Centre of Excellence, Trg Osvobodilne fronte 13, Ljubljana 1000, Slovenia; Corresponding author: Duško Lainšček, Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, Ljubljana 1000, Slovenia.Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, Ljubljana 1000, SloveniaDepartment of Hematology, Division of Internal Medicine, University Medical Center Ljubljana, Zaloška 7, Ljubljana 1000, Slovenia; Graduate School of Biomedicine, University of Ljubljana, Ljubljana 1000, SloveniaDepartment of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, Ljubljana 1000, Slovenia; Graduate School of Biomedicine, University of Ljubljana, Ljubljana 1000, SloveniaDepartment of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, Ljubljana 1000, Slovenia; Graduate School of Biomedicine, University of Ljubljana, Ljubljana 1000, SloveniaDepartment of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, Ljubljana 1000, Slovenia; EN-FIST Centre of Excellence, Trg Osvobodilne fronte 13, Ljubljana 1000, Slovenia; Corresponding author: Roman Jerala, Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, Ljubljana 1000, Slovenia.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.http://www.sciencedirect.com/science/article/pii/S237277052300030XCD19 CAR-T cellscancer immunotherapyheterodimerization systempharmacological controlNFATartificial transcription factors |
| spellingShingle | Duško Lainšček Anja Golob-Urbanc Veronika Mikolič Jelica Pantović-Žalig Špela Malenšek Roman Jerala Regulation of CD19 CAR-T cell activation based on an engineered downstream transcription factor Molecular Therapy: Oncolytics CD19 CAR-T cells cancer immunotherapy heterodimerization system pharmacological control NFAT artificial transcription factors |
| title | Regulation of CD19 CAR-T cell activation based on an engineered downstream transcription factor |
| title_full | Regulation of CD19 CAR-T cell activation based on an engineered downstream transcription factor |
| title_fullStr | Regulation of CD19 CAR-T cell activation based on an engineered downstream transcription factor |
| title_full_unstemmed | Regulation of CD19 CAR-T cell activation based on an engineered downstream transcription factor |
| title_short | Regulation of CD19 CAR-T cell activation based on an engineered downstream transcription factor |
| title_sort | regulation of cd19 car t cell activation based on an engineered downstream transcription factor |
| topic | CD19 CAR-T cells cancer immunotherapy heterodimerization system pharmacological control NFAT artificial transcription factors |
| url | http://www.sciencedirect.com/science/article/pii/S237277052300030X |
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