Neurotoxicity
CAR T-related neurotoxicity, also known as immune effector cell (IEC) therapy-associated neurotoxicity syndrome (ICANS), is pathophysiologically distinct from CRS 34. Symptoms observed are global encephalopathy, which can include aphasia, confusion, hallucination, tremor, and agitation; focal deficits; and seizures 19,21,35. While the pathophysiology of neurotoxicity remains to be fully elucidated, it is hypothesized to be an off-target toxicity with some evidence to suggest the diffusion of inflammatory cytokines through the blood-brain barrier and/or direct CNS toxicity by the engineered T cells may play a role 36. In limited available data, ICANS does not appear to be readily reversed or ameliorated by IL-6 receptor blockade, possibly due to upregulation of IL-6, inefficient distribution into the CNS (as most monoclonal antibodies do not cross blood brain barrier), or the involvement of other cytokines. Furthermore, although it is known that tisagenlecleucel crosses the blood brain barrier and can persist for months, no clear correlation exists between the presence of tisagenlecleucel in the CNS and severity of symptoms 37,38. Treatment for ICANS is mainly focused on supportive care after ruling out other potential causes of symptoms 31.