Management of CAR T-cell related toxicities: What did the learning curve teach us so far?

From spear to trident: Upgrading arsenal of CAR-T cells in the treatment of multiple myeloma

“…Most CARs designed to target tumor-associated antigens inevitably result in some form of on-target/off-target toxicity (OTOT) [ 89 ]. In addition, the potential for cytokine-related toxicities [ 90 ] may be another overlooked but expected outcome of OTOT reactions. Based on these, we review some of the more common toxicity risks [ 90 ], including OTOT toxicities, cytokine release syndrome and certain neurological events associated with CAR therapy.…”

“…The clinical features observed in CRS share many similarities with macrophage activation syndrome and hemophagocytic lymphohistiocytosis (HLH) [ 96 ]. In addition to the common clinical features observed between HLH and CRS [ 90 ], the main cytokines that are increased in HLH [ 97 ] are mild to severe, including multi-organ damage, IL10, IL6 and IFNγ. Increased levels of these cytokines after CAR-T infusion indicate macrophage activation and a possible role for macrophages in driving certain aspects of CRS.…”

“…Emerged as an unexpected outcome linked with CAR therapy, neurotoxicity has been observed in relation to CRS or immediately after the development of CRS and following the resolution of CRS or without any CRS. Neurologic toxicities caused by CAR therapy are diverse and include encephalopathy, cognitive defects, dysphasias, seizures, and cerebral edema [ 90 , 98 ]. Requiring intubation and mechanical ventilation, these neurological complications may become severe.…”

Immune Effector Cell-Associated HLH-like Syndrome: A Review of the Literature of an Increasingly Recognized Entity

“…The monoclonal antibody tocilizumab disrupts downstream IL-6 signaling by binding to the IL-6 receptors, which may interrupt the pro-inflammatory signaling inherent to the development of CRS [67]. Despite strong evidence for its use in CRS, small studies attempting to characterize its effect in IEC-HS trouble the notion of its use in the absence of other active inflammatory complications.…”

“…Further lines of treatment with emapalumab and/or cytotoxic anti-T-cell agents may be considered in refractory cases, although data in IEC-HS are lacking. The utilization of other novel anti-inflammatory agents and treatment strategies for HLH that may be applicable in IEC-HS is an area of ongoing study [67].…”