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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.
- Source :
-
Cells (2073-4409) . Nov2023, Vol. 12 Issue 21, p2581. 15p. - Publication Year :
- 2023
-
Abstract
- 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 20734409
- Volume :
- 12
- Issue :
- 21
- Database :
- Academic Search Index
- Journal :
- Cells (2073-4409)
- Publication Type :
- Academic Journal
- Accession number :
- 173569255
- Full Text :
- https://doi.org/10.3390/cells12212581