Early induction of cytokine release syndrome by rapidly generated CAR T cells in preclinical models
© 2024. The Author(s)..
Cytokine release syndrome (CRS) is a significant side-effect of conventional chimeric antigen receptor (CAR) T-cell therapy. To facilitate patient accessibility, short-term (st) CAR T cells, which are administered to patients only 24 h after vector exposure, are in focus of current investigations. Their impact on the incidence and severity of CRS has been poorly explored. Here, we evaluated CD19-specific stCAR T cells in preclinical models. In co-culture with tumor cells and monocytes, stCAR T cells exhibited anti-tumoral activity and potent release of CRS-related cytokines (IL-6, IFN-γ, TNF-α, GM-CSF, IL-2, IL-10). When administered to NSG-SGM3 mice, stCAR T cells, but not conventional CAR T cells, induced severe acute adverse events within 24 h, including hypothermia and weight loss, as well as high body scores, independent of the presence of tumor target cells. Human (IFN-γ, TNF-α, IL-2, IL-10) and murine (MCP-1, IL-6, G-CSF) cytokines, typical for severe CRS, were systemically elevated. Our data highlight potential safety risks of rapidly manufactured CAR T cells and suggest NSG-SGM3 mice as sensitive model for their preclinical safety evaluation.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:16 |
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| Enthalten in: |
EMBO molecular medicine - 16(2024), 4 vom: 21. Apr., Seite 784-804 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Jamali, Arezoo [VerfasserIn] |
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| Links: |
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| Themen: |
130068-27-8 |
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| Anmerkungen: |
Date Completed 17.04.2024 Date Revised 18.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s44321-024-00055-9 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM370043693 |
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| 520 | |a Cytokine release syndrome (CRS) is a significant side-effect of conventional chimeric antigen receptor (CAR) T-cell therapy. To facilitate patient accessibility, short-term (st) CAR T cells, which are administered to patients only 24 h after vector exposure, are in focus of current investigations. Their impact on the incidence and severity of CRS has been poorly explored. Here, we evaluated CD19-specific stCAR T cells in preclinical models. In co-culture with tumor cells and monocytes, stCAR T cells exhibited anti-tumoral activity and potent release of CRS-related cytokines (IL-6, IFN-γ, TNF-α, GM-CSF, IL-2, IL-10). When administered to NSG-SGM3 mice, stCAR T cells, but not conventional CAR T cells, induced severe acute adverse events within 24 h, including hypothermia and weight loss, as well as high body scores, independent of the presence of tumor target cells. Human (IFN-γ, TNF-α, IL-2, IL-10) and murine (MCP-1, IL-6, G-CSF) cytokines, typical for severe CRS, were systemically elevated. Our data highlight potential safety risks of rapidly manufactured CAR T cells and suggest NSG-SGM3 mice as sensitive model for their preclinical safety evaluation | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a CRS Model | |
| 650 | 4 | |a Myeloid Cells | |
| 650 | 4 | |a NSG-SGM3 Mouse Model | |
| 650 | 4 | |a Rapid Manufactured CAR T Cell | |
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| 700 | 1 | |a Thalheimer, Frederic B |e verfasserin |4 aut | |
| 700 | 1 | |a Buchholz, Christian J |e verfasserin |4 aut | |
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