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CAR T cell related cytokine release syndrome mouse model

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE111236 | GEO | 2018/05/28

REPOSITORIES: GEO

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