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Cell-based models of ‘Cytokine Release Syndrome’ endorse CD40L and GM-CSF knockout in CAR T cells as mitigation strategy

ABSTRACT: Chimeric antigen receptor (CAR) T cells are engineered lymphocytes able to recognize and eradicate cancer cells. While CAR T cell therapy has shown promising outcomes in patients with hematologic malignancies, it can cause 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 pro-inflammatory cytokines. Mouse models have been used to model CRS but they are labor intensive and not amenable to screening approaches. To overcome this challenge, we established two 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 GM-CSF which stimulated the monocytes to release 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. Overall, our cell-based models were able to recapitulate CRS in vitro, allowing us to validate mitigation strategies based on antibodies or genome editing.

ORGANISM(S): Homo sapiens

PROVIDER: GSE243587 | GEO | 2023/12/06

REPOSITORIES: GEO

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