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CAR T Cell Sytotoxic Supernatant Stimulates Monocytes to Drive Cytokine Storm

ABSTRACT: Chimeric antigen receptor (CAR) T cell-therapy is substantially constrained by cytokine release syndrome (CRS). The precise mechanisms underlying CAR T cell-therapy-associated CRS remain elusive. Here, we show that CAR T cell-induced tumor cytotoxicity activates monocytes to release IL-1β, IL-6, and TNF-α, key inflammatory cytokines driving CRS, via monocyte contact-independent manner.

ORGANISM(S): Homo sapiens

PROVIDER: GSE302543 | GEO | 2025/07/20

REPOSITORIES: GEO

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Project description:Chimeric antigen receptor (CAR) therapy targeting CD19 is an effective treatment for refractory B cell malignancies, especially acute lymphoblastic leukemia (ALL). While a majority of patients will achieve a complete response following a single infusion of CD19 CAR T cells, the broad applicability of this treatment is hampered by severe cytokine release syndrome (CRS), which is characterised by fever, hypotension and respiratory insufficiency associated with elevated serum cytokines including interleukin-6 (IL-6). CRS usually occurs within days of T cell infusion at the peak of CAR T cell expansion. In ALL, it is most frequent and more severe in patients with high tumour burden CRS is often responsive to IL-6 receptor blockade, but may require intensive life support and further treatment with high dose corticosteroids to prevent potentially lethal severity. Improved therapeutic and preventive treatments require a better understanding of CRS physiopathology, which has so far remained elusive. We report here a murine model of CRS that develops within 2-3 days of CAR T cell infusion, may be lethal and is responsive to IL-6 receptor blockade. We show that its severity is mediated not by CAR T cell-derived cytokines but by IL-6, interleukin-1 (IL-1) and Nitric Oxide (NO) produced by recipient macrophages. This CRS mechanism enables novel therapeutic interventions.

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

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CAR T Cell Sytotoxic Supernatant Stimulates Monocytes to Drive Cytokine Storm

Project description:CAR T Cell Sytotoxic Supernatant Stimulates Monocytes to Drive Cytokine Storm

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Gene expression profile of CD22 CAR T-cell products

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