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Nat Med. 2018 Jun;24(6):731-738. doi: 10.1038/s41591-018-0041-7. Epub 2018 May 28.

CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade.

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Center for Cell Engineering and Immunology Program, Sloan Kettering Institute, New York, NY, USA.
Laboratory of Comparative Pathology, Rockefeller University, Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Center for Cell Engineering and Immunology Program, Sloan Kettering Institute, New York, NY, USA.


Chimeric antigen receptor (CAR) therapy targeting CD19 is an effective treatment for refractory B cell malignancies, especially acute lymphoblastic leukemia (ALL) 1 . Although a majority of patients will achieve a complete response following a single infusion of CD19-targeted CAR-modified T cells (CD19 CAR T cells)2-4, the broad applicability of this treatment is hampered by severe cytokine release syndrome (CRS), which is characterized by fever, hypotension and respiratory insufficiency associated with elevated serum cytokines, including interleukin-6 (IL-6)2,5. 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 tumor burden2-4. CRS may respond to IL-6 receptor blockade but can require further treatment with high dose corticosteroids to curb potentially lethal severity2-9. Improved therapeutic and preventive treatments require a better understanding of CRS physiopathology, which has so far remained elusive. Here we report a murine model of CRS that develops within 2-3 d of CAR T cell infusion and that is potentially lethal and responsive to IL-6 receptor blockade. We show that its severity is mediated not by CAR T cell-derived cytokines, but by IL-6, IL-1 and nitric oxide (NO) produced by recipient macrophages, which enables new therapeutic interventions.

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