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- Title
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.
- Authors
Dibas, Ala; Rhiel, Manuel; Patel, Vidisha Bhavesh; Andrieux, Geoffroy; Boerries, Melanie; Cornu, Tatjana I.; Alzubi, Jamal; Cathomen, Toni
- 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.
- Subjects
GRANULOCYTE-macrophage colony-stimulating factor; CYTOKINE release syndrome; T cells; CHIMERIC antigen receptors; T cell receptors; B cells; MONOCYTES
- Publication
Cells (2073-4409), 2023, Vol 12, Issue 21, p2581
- ISSN
2073-4409
- Publication type
Article
- DOI
10.3390/cells12212581