Mechanisms and strategies for safe chimeric antigen receptor T-cell activity control
© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC..
The clinical application of chimeric antigen receptor (CAR) T-cell therapy has rapidly changed the treatment options for terminally ill patients with defined blood-borne cancer types. However, CAR T-cell therapy can lead to severe therapy-associated toxicities including CAR-related hematotoxicity, ON-target OFF-tumor toxicity, cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Just as CAR T-cell therapy has evolved regarding receptor design, gene transfer systems and production protocols, the management of side effects has also improved. However, because of measures taken to abrogate adverse events, CAR T-cell viability and persistence might be impaired before complete remission can be achieved. This has fueled efforts for the development of extrinsic and intrinsic strategies for better control of CAR T-cell activity. These approaches can mediate a reversible resting state or irreversible T-cell elimination, depending on the route chosen. Control can be passive or active. By combination of CAR T-cells with T-cell inhibiting compounds, pharmacologic control, mostly independent of the CAR construct design used, can be achieved. Other strategies involve the genetic modification of T-cells or further development of the CAR construct by integration of molecular ON/OFF switches such as suicide genes. Alternatively, CAR T-cell activity can be regulated intracellularly through a self-regulation function or extracellularly through titration of a CAR adaptor or of a priming small molecule. In this work, we review the current strategies and mechanisms to control activity of CAR T-cells reversibly or irreversibly for preventing and for managing therapy-associated toxicities.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:153 |
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| Enthalten in: |
International journal of cancer - 153(2023), 10 vom: 15. Nov., Seite 1706-1725 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Stock, Sophia [VerfasserIn] |
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| Links: |
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| Themen: |
Adoptive T-cell therapy |
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| Anmerkungen: |
Date Completed 19.09.2023 Date Revised 19.09.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/ijc.34635 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a © 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC. | ||
| 520 | |a The clinical application of chimeric antigen receptor (CAR) T-cell therapy has rapidly changed the treatment options for terminally ill patients with defined blood-borne cancer types. However, CAR T-cell therapy can lead to severe therapy-associated toxicities including CAR-related hematotoxicity, ON-target OFF-tumor toxicity, cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Just as CAR T-cell therapy has evolved regarding receptor design, gene transfer systems and production protocols, the management of side effects has also improved. However, because of measures taken to abrogate adverse events, CAR T-cell viability and persistence might be impaired before complete remission can be achieved. This has fueled efforts for the development of extrinsic and intrinsic strategies for better control of CAR T-cell activity. These approaches can mediate a reversible resting state or irreversible T-cell elimination, depending on the route chosen. Control can be passive or active. By combination of CAR T-cells with T-cell inhibiting compounds, pharmacologic control, mostly independent of the CAR construct design used, can be achieved. Other strategies involve the genetic modification of T-cells or further development of the CAR construct by integration of molecular ON/OFF switches such as suicide genes. Alternatively, CAR T-cell activity can be regulated intracellularly through a self-regulation function or extracellularly through titration of a CAR adaptor or of a priming small molecule. In this work, we review the current strategies and mechanisms to control activity of CAR T-cells reversibly or irreversibly for preventing and for managing therapy-associated toxicities | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 650 | 4 | |a adoptive T-cell therapy | |
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| 700 | 1 | |a Menkhoff, Vivien D |e verfasserin |4 aut | |
| 700 | 1 | |a Subklewe, Marion |e verfasserin |4 aut | |
| 700 | 1 | |a Endres, Stefan |e verfasserin |4 aut | |
| 700 | 1 | |a Kobold, Sebastian |e verfasserin |4 aut | |
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