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

   


Authors: Giavridis, T.; van der Stegen, S. J. C.; Eyquem, J.; Hamieh, M.; Piersigilli, A.; Sadelain, M.
Article Title: CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade
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 burden 2-4 . CRS may respond to IL-6 receptor blockade but can require further treatment with high dose corticosteroids to curb potentially lethal severity 2-9 . 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. © 2018 The Author(s).
Journal Title: Nature Medicine
Volume: 24
Issue: 6
ISSN: 1078-8956
Publisher: Nature Publishing Group  
Date Published: 2018-06-01
Start Page: 731
End Page: 738
Language: English
DOI: 10.1038/s41591-018-0041-7
PROVIDER: scopus
PUBMED: 29808005
PMCID: PMC6410714
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85047803079&doi=10.1038%2fs41591-018-0041-7&partnerID=40&md5=111d9ddc403911b9fe2660d1d2079a06
Notes: Article -- Export Date: 2 July 2018 -- Source: Scopus
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MSK Authors
  1. Michel W J Sadelain
    583 Sadelain
  2. Mohamad Hamieh
    27 Hamieh
  3. Sjoukje Judith Catherina van der Stegen
    26 van der Stegen
  4. Justin Gabriel Andre Francois Eyquem
    25 Eyquem
  5. Theodoros Giavridis
    12 Giavridis
  6. Alessandra Piersigilli
    15 Piersigilli
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