Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Jun;24(6):739-748.
doi: 10.1038/s41591-018-0036-4. Epub 2018 May 28.

Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells

Margherita Norelli  1   2 , Barbara Camisa  1 , Giulia Barbiera  3 , Laura Falcone  1 , Ayurzana Purevdorj  1 , Marco Genua  3 , Francesca Sanvito  4 , Maurilio Ponzoni  4 , Claudio Doglioni  4 , Patrizia Cristofori  5 , Catia Traversari  6 , Claudio Bordignon  2   6 , Fabio Ciceri  2   7 , Renato Ostuni  3 , Chiara Bonini  2   8 , Monica Casucci  1 , Attilio Bondanza  9   10
Affiliations

Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells

Margherita Norelli et al. Nat Med. 2018 Jun.

Abstract

In the clinic, chimeric antigen receptor-modified T (CAR T) cell therapy is frequently associated with life-threatening cytokine-release syndrome (CRS) and neurotoxicity. Understanding the nature of these pathologies and developing treatments for them are hampered by the lack of appropriate animal models. Herein, we describe a mouse model recapitulating key features of CRS and neurotoxicity. In humanized mice with high leukemia burden, CAR T cell-mediated clearance of cancer triggered high fever and elevated IL-6 levels, which are hallmarks of CRS. Human monocytes were the major source of IL-1 and IL-6 during CRS. Accordingly, the syndrome was prevented by monocyte depletion or by blocking IL-6 receptor with tocilizumab. Nonetheless, tocilizumab failed to protect mice from delayed lethal neurotoxicity, characterized by meningeal inflammation. Instead, the IL-1 receptor antagonist anakinra abolished both CRS and neurotoxicity, resulting in substantially extended leukemia-free survival. These findings offer a therapeutic strategy to tackle neurotoxicity and open new avenues to safer CAR T cell therapies.

PubMed Disclaimer

Comment in

  • Modeling cytokine release syndrome.
    Rooney C, Sauer T. Rooney C, et al. Nat Med. 2018 Jun;24(6):705-706. doi: 10.1038/s41591-018-0068-9. Nat Med. 2018. PMID: 29808004 No abstract available.
  • Calming the cytokine storm.
    Bird L. Bird L. Nat Rev Immunol. 2018 Jul;18(7):417. doi: 10.1038/s41577-018-0030-6. Nat Rev Immunol. 2018. PMID: 29899366 No abstract available.

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

Publication types

MeSH terms

LinkOut - more resources

-