Understanding the Mechanisms of CAR T-Cell Toxicities for Their Prevention and Management

Despite the successes of chimeric antigen receptor (CAR) T-cell therapy against hematologic malignancies, toxicities continue to limit the therapy’s potential. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are the two most significant toxicities, both in terms of how common they are and how dangerous.
A recent review article in the Journal of Experimental and Clinical Cancer Research reviewed the mechanisms of CRS and ICANS, then offered potential approaches to prevent and manage them.
CRS is a systemic inflammatory response believed to be mediated by overactivation of effector cells and large amounts of cytokines, such as interleukin (IL)-1, IL-6, interferon (IFN)-gamma and granulocyte-macrophage colony-stimulating factor (GM-CSF).
“The interplay between CAR T-cells and tumor cells activates host bystander cells, especially macrophages, eliciting a distortion of the cytokine network. Then, massive cytokines induce endothelial cell activation, contributing to constitutional symptoms in relation to CRS,” wrote the authors, led by Xinyi Xiao, of the Second School of Clinical Medicine, Zhujiang Hospital, Southern Medical University, in Guangzhou, China.
CAR T-cell neurotoxicity (named ICANS by the American Society for Transplantation and Cellular Therapy) is a toxic encephalopathy with a variety of neuropsychiatric symptoms. It is related to CRS, occurring and peaking several days after CRS begins.
“It appears that the activation of the cerebral vascular endothelium and disruption of the brain-blood barrier occur at the onset of ICANS,” the authors wrote. “Without the barrier function of the [brain-blood barrier], extensive numbers of immune cells and cytokines infiltrate the CNS. Together with activated resident proinflammatory cells, infiltrated immune cells exacerbate the inflammatory cascade in the CNS, accounting for the cerebral edema, thrombosis, hemolysis, and other neuropsychiatric symptoms observed in ICANS.”
The authors offered several strategies to prevent and manage CRS and ICANS, based on the mechanisms as they are understood at the current time:
• optimizing the infusion dose
• optimizing CAR structure
• adding switches on CAR T-cells to regulate the inactivation of CAR signaling
• targeting IL-1 and IL-6 , GM-CSF, and/or the JAK signaling pathway with agents such as tocilizumab, siltuximab, anakinra, lenzilumab, and others
• using corticosteroids to reduce the incidence of severe toxicities
The authors called for more research to understand the toxicities, including why some cases are reversible but others are fatal.
“Animal models play critical roles in both further understanding the detailed mechanisms of toxicities and exploring promising strategies. Rapid progress is underway in the optimization of the modeling, including humanized mice and primate models, in an effort to narrow the gap with clinical settings,” the authors wrote. “In addition, advances in sequencing and omics techniques provide new insight into mechanistic studies. Such techniques can help identify certain cell populations and components that cannot be identified by traditional technologies.”