Cell-Based Models of 'Cytokine Release Syndrome' Endorse CD40L and Granulocyte-Macrophage Colony-Stimulating Factor Knockout in Chimeric Antigen Receptor T Cells as Mitigation Strategy
While chimeric antigen receptor (CAR) T cell therapy has shown promising outcomes among patients with hematologic malignancies, it has also been associated with undesirable side-effects such as cytokine release syndrome (CRS). CRS is triggered by CAR T-cell-based activation of monocytes, which are stimulated via the CD40L-CD40R axis or via uptake of GM-CSF to secrete proinflammatory cytokines. Mouse models have been used to model CRS, but working with them is labor-intensive and they are not amenable to screening approaches. To overcome this challenge, we established two simple cell-based CRS in vitro models that entail the co-culturing of leukemic B cells with CD19-targeting CAR T cells and primary monocytes from the same donor. Upon antigen encounter, CAR T cells upregulated CD40L and released GM-CSF which in turn stimulated the monocytes to secrete IL-6. To endorse these models, we demonstrated that neutralizing antibodies or genetic disruption of the CD40L and/or CSF2 loci in CAR T cells using CRISPR-Cas technology significantly reduced IL-6 secretion by bystander monocytes without affecting the cytolytic activity of the engineered lymphocytes in vitro. Overall, our cell-based models were able to recapitulate CRS in vitro, allowing us to validate mitigation strategies based on antibodies or genome editing.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
Cells - 12(2023), 21 vom: 06. Nov. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Dibas, Ala [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 13.11.2023 Date Revised 01.02.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.3390/cells12212581 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM364393270 |
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| 245 | 1 | 0 | |a Cell-Based Models of 'Cytokine Release Syndrome' Endorse CD40L and Granulocyte-Macrophage Colony-Stimulating Factor Knockout in Chimeric Antigen Receptor T Cells as Mitigation Strategy |
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| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a While chimeric antigen receptor (CAR) T cell therapy has shown promising outcomes among patients with hematologic malignancies, it has also been associated with undesirable side-effects such as cytokine release syndrome (CRS). CRS is triggered by CAR T-cell-based activation of monocytes, which are stimulated via the CD40L-CD40R axis or via uptake of GM-CSF to secrete proinflammatory cytokines. Mouse models have been used to model CRS, but working with them is labor-intensive and they are not amenable to screening approaches. To overcome this challenge, we established two simple cell-based CRS in vitro models that entail the co-culturing of leukemic B cells with CD19-targeting CAR T cells and primary monocytes from the same donor. Upon antigen encounter, CAR T cells upregulated CD40L and released GM-CSF which in turn stimulated the monocytes to secrete IL-6. To endorse these models, we demonstrated that neutralizing antibodies or genetic disruption of the CD40L and/or CSF2 loci in CAR T cells using CRISPR-Cas technology significantly reduced IL-6 secretion by bystander monocytes without affecting the cytolytic activity of the engineered lymphocytes in vitro. Overall, our cell-based models were able to recapitulate CRS in vitro, allowing us to validate mitigation strategies based on antibodies or genome editing | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a CD19-CAR T cells | |
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| 650 | 4 | |a CRISPR-Cas9 | |
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| 700 | 1 | |a Rhiel, Manuel |e verfasserin |4 aut | |
| 700 | 1 | |a Patel, Vidisha Bhavesh |e verfasserin |4 aut | |
| 700 | 1 | |a Andrieux, Geoffroy |e verfasserin |4 aut | |
| 700 | 1 | |a Boerries, Melanie |e verfasserin |4 aut | |
| 700 | 1 | |a Cornu, Tatjana I |e verfasserin |4 aut | |
| 700 | 1 | |a Alzubi, Jamal |e verfasserin |4 aut | |
| 700 | 1 | |a Cathomen, Toni |e verfasserin |4 aut | |
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