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

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.

• Authors: Margherita Norelli, Barbara Camisa, Giulia Barbiera, Laura Falcone, Ayurzana Purevdorj, Marco Genua, Francesca Sanvito, Maurilio Ponzoni, Claudio Doglioni, Patrizia Cristofori, Catia Traversari, Claudio Bordignon, Fabio Ciceri, Renato Ostuni, Chiara Bonini, Monica Casucci, Attilio Bondanza
• Journal: Nature medicine (Nat Med) Vol. 24 Issue 6 Pg. 739-748 (06 2018) ISSN: 1546-170X [Electronic] United States
• PMID: 29808007 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• Interleukin 1 Receptor Antagonist Protein
• Interleukin-1
• Interleukin-6
• Neurotoxins
• Receptors, Chimeric Antigen
• tocilizumab

Topics

• Animals
• Animals, Newborn
• Antibodies, Monoclonal, Humanized (pharmacology, therapeutic use)
• Cell Line, Tumor
• Hematopoietic Stem Cells (metabolism)
• Humans
• Immunotherapy, Adoptive (adverse effects)
• Interleukin 1 Receptor Antagonist Protein (pharmacology, therapeutic use)
• Interleukin-1 (metabolism)
• Interleukin-6 (metabolism)
• Leukemia (immunology, pathology)
• Mice
• Monocytes (metabolism)
• Neurotoxins (toxicity)
• Receptors, Chimeric Antigen (metabolism)
• Syndrome