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.

A retrospective comparison of allogenic and autologous chimeric antigen receptor T cell therapy targeting CD19 in patients with relapsed/refractory acute lymphoblastic leukemia

“…None of these factors had significant difference between the groups in our study. The difference could be explained partially by the fact that autoCAR T cells had more robust [26,27]. However, Tcell function was suppressed by monocytes post-HSCT [28], which may result in less severe CRS.…”

Adoptive CD8+ T cell therapy against cancer:Challenges and opportunities

“…CAR-T-related encephalopathy syndrome (CRES) is the most severe neurological syndrome and its development is critically dependent on monocytes-derived IL-1 and IL-6. Neutralizing these two cytokines reversed CRES effectively [81]. The inflammatory cytokines may activate endothelial cells of the blood-brain barrier and disrupt the barrier integrity, and endothelial cell activation in the central nervous system might drive the CAR-T therapy associated neurotoxicity [91].…”

“…CRS is characterized by high fever, skin rash, hypotension, hypoxia, cardiac dysfunction, kidney failure, electrolyte abnormalities and neurologic symptoms, even death [80]. The use of Glucocorticoids and/or antibodies blocking IL-1 receptor (Anakinra) and IL-6 receptor (Tocilizumab), but not IFN-γ and TNF-α, could effectively reverse CRS [81,82].…”

Next Generation of Cancer Treatments: Chimeric Antigen Receptor T-Cell Therapy and Its Related Toxicities: A Review for Perioperative Physicians

“…31 43 Thus, its use in patients experiencing neurotoxicity may be detrimental. 40,44 The most severe manifestations of neurotoxicity include refractory seizure activity and life-threatening cerebral edema. [38][39][40] Multiple fatalities from brain herniation lead to the early termination of the 2016 anti-CD19 CAR Study Evaluating the Efficacy and Safety of JCAR015 in Adult B-cell Acute Lymphoblastic Leukemia (B-ALL) (ROCKET) trial.…”