Chemical genetic control of cytokine signaling in CAR-T cells using lenalidomide-controlled membrane-bound degradable IL-7
© 2023. The Author(s), under exclusive licence to Springer Nature Limited..
CAR-T cell therapy has emerged as a breakthrough therapy for the treatment of relapsed and refractory hematologic malignancies. However, insufficient CAR-T cell expansion and persistence is a leading cause of treatment failure. Exogenous or transgenic cytokines have great potential to enhance CAR-T cell potency but pose the risk of exacerbating toxicities. Here we present a chemical-genetic system for spatiotemporal control of cytokine function gated by the off-patent anti-cancer molecular glue degrader drug lenalidomide and its analogs. When co-delivered with a CAR, a membrane-bound, lenalidomide-degradable IL-7 fusion protein enforced a clinically favorable T cell phenotype, enhanced antigen-dependent proliferative capacity, and enhanced in vivo tumor control. Furthermore, cyclical pharmacologic combined control of CAR and cytokine abundance enabled the deployment of highly active, IL-7-augmented CAR-T cells in a dual model of antitumor potency and T cell hyperproliferation.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:38 |
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| Enthalten in: |
Leukemia - 38(2024), 3 vom: 15. März, Seite 590-600 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kann, Michael C [VerfasserIn] |
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| Links: |
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| Themen: |
Cytokines |
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| Anmerkungen: |
Date Completed 06.03.2024 Date Revised 25.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41375-023-02113-6 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM366143603 |
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| 520 | |a CAR-T cell therapy has emerged as a breakthrough therapy for the treatment of relapsed and refractory hematologic malignancies. However, insufficient CAR-T cell expansion and persistence is a leading cause of treatment failure. Exogenous or transgenic cytokines have great potential to enhance CAR-T cell potency but pose the risk of exacerbating toxicities. Here we present a chemical-genetic system for spatiotemporal control of cytokine function gated by the off-patent anti-cancer molecular glue degrader drug lenalidomide and its analogs. When co-delivered with a CAR, a membrane-bound, lenalidomide-degradable IL-7 fusion protein enforced a clinically favorable T cell phenotype, enhanced antigen-dependent proliferative capacity, and enhanced in vivo tumor control. Furthermore, cyclical pharmacologic combined control of CAR and cytokine abundance enabled the deployment of highly active, IL-7-augmented CAR-T cells in a dual model of antitumor potency and T cell hyperproliferation | ||
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| 700 | 1 | |a Almazan, Antonio J |e verfasserin |4 aut | |
| 700 | 1 | |a Lane, Isabel C |e verfasserin |4 aut | |
| 700 | 1 | |a Bouffard, Amanda A |e verfasserin |4 aut | |
| 700 | 1 | |a Supper, Valentina M |e verfasserin |4 aut | |
| 700 | 1 | |a Takei, Hana N |e verfasserin |4 aut | |
| 700 | 1 | |a Tepper, Alexander |e verfasserin |4 aut | |
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| 700 | 1 | |a Maus, Marcela V |e verfasserin |4 aut | |
| 700 | 1 | |a Jan, Max |e verfasserin |4 aut | |
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