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.