CAR T cell–induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. (June 2018)

• Record Type: Journal Article
• Authors: Giavridis, Theodoros; van der Stegen, Sjoukje; Eyquem, Justin; Hamieh, Mohamad; Piersigilli, Alessandra; Sadelain, Michel
• Is Part Of: Nature medicine. Volume 24:Number 6(2018)
• Page Start: 731
• Page End: 738
• Publication Date: 2018-06
• Subjects: Pathology, Molecular -- Periodicals; Molecular biology -- Periodicals; 610.724
• DOI: 10.1038/s41591-018-0041-7
• Languages: English
• ISSNs: 1078-8956

Abstract

Abstract 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. Blocking IL-1 and iNOS prevents CAR T cell–induced cytokine release syndrome.