From the Guidelines
CD19 is not expressed in the brain under normal conditions, which is crucial for understanding neuroinflammation related to CAR-T therapy. CD19 is primarily found on B cells and B cell malignancies, not on neurons or glial cells in the central nervous system. However, neuroinflammation during CAR-T therapy (particularly CD19-targeted therapy) occurs through mechanisms independent of direct CD19 targeting in the brain. The neuroinflammation is primarily caused by cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), where activated CAR-T cells release inflammatory cytokines that can cross the blood-brain barrier and activate microglia and other brain immune cells.
Key Points
- CD19-targeted CAR T cells can cause ICANS, which includes encephalopathy, expressive aphasia, dysgraphia, and other neurological symptoms 1.
- The ICANS grading system incorporates the 10-point Immune Effector Cell–Associated Encephalopathy (ICE) score and evaluation of other neurologic domains, including level of consciousness and seizures 1.
- The mainstay of treatment of ICANS is supportive care and corticosteroids, as tocilizumab may worsen neurotoxicity 1. Some research has detected very low levels of CD19 mRNA in certain brain regions, but this doesn't translate to significant protein expression.
Mechanisms of Neurotoxicity
- The inflammatory cascade, rather than direct CD19 targeting, leads to neurological symptoms during CAR-T therapy.
- Activated CAR-T cells release inflammatory cytokines that can cross the blood-brain barrier and activate microglia and other brain immune cells. The study by 1 provides guidance on the management of immune-related adverse events in patients treated with chimeric antigen receptor T-cell therapy, including ICANS.
From the Research
CD19 Expression in the Brain
- There is no direct evidence in the provided studies that CD19 is expressed in the brain.
- The studies focus on the treatment of CD19-positive malignancies using CAR-T cell therapy and the associated adverse events, such as cytokine release syndrome (CRS) and neurotoxicity 2, 3, 4.
- One study mentions the treatment of central nervous system B-cell acute lymphocytic leukemia (CNS B-ALL) with CAR-T cells targeting CD19, but it does not provide information on CD19 expression in the brain 5.
Neuroinflammation due to CAR-T Cell Therapy
- CAR-T cell therapy has been associated with neurologic events, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) 2, 3.
- The studies suggest that neurotoxicity is a common toxicity associated with CD19 CAR-T cell therapies, but they do not provide information on the expression of CD19 in the brain 3, 4.
- One study discusses the use of IL-6 blockade to alleviate the cytokine storm induced by CAR-T cell therapy, which may be relevant to understanding neuroinflammation due to CAR-T cell therapy 6.