CAR T Neurotoxicity: Mechanisms, Challenges, and Patterns

CAR T-cell therapy has transformed cancer treatment, particularly for hematologic malignancies. However, its success comes with significant toxicities, including neurotoxicity, which ranges from mild confusion to severe cerebral edema. Understanding these effects is crucial for improving patient outcomes and refining therapeutic strategies.

Mechanisms Of Neuroinflammation

Neuroinflammation in CAR T-cell therapy results from a complex interplay of cellular and molecular events that disrupt normal brain function. A primary driver is the excessive release of cytokines, particularly interleukin-6 (IL-6), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α). These pro-inflammatory mediators contribute to endothelial activation and increased vascular permeability, allowing immune cells to infiltrate the central nervous system (CNS) and amplify inflammation.

Microglial activation sustains this response. As resident immune cells of the CNS, microglia become hyperactivated, releasing additional cytokines and reactive oxygen species (ROS), leading to neuronal damage and synaptic dysfunction. Studies have linked excessive microglial activation to more severe neurotoxicity, suggesting that targeting these cells could offer therapeutic benefits.

Astrocyte dysregulation also plays a role. Under inflammatory conditions, astrocytes shift to a reactive state, producing chemokines that recruit immune cells into the brain. This reactive gliosis disrupts neural networks, leading to cognitive impairment and encephalopathy. Elevated levels of glial fibrillary acidic protein (GFAP), a marker of astrocyte activation, correlate with more severe neurotoxicity, reinforcing the role of astrocytic dysfunction.

Blood-Brain Barrier Factors

The blood-brain barrier (BBB) regulates the passage of molecules between the bloodstream and the CNS, maintaining homeostasis and protecting neural tissue. During CAR T-cell therapy, BBB disruptions allow neurotoxic effects to manifest more readily, worsening neurological symptoms.

Endothelial dysfunction is an early sign of BBB compromise. The tight junction proteins occludin, claudins, and zonula occludens-1 (ZO-1) maintain vascular integrity, but inflammatory signaling triggered by CAR T-cell activation degrades these proteins, increasing permeability. Elevated levels of angiopoietin-2 (Ang-2), a marker of endothelial destabilization, have been identified in patients with severe neurotoxicity, highlighting vascular integrity loss as a key factor. This breakdown permits unregulated entry of cytokines, immune cells, and other circulating factors into the CNS, exacerbating inflammation and neuronal dysfunction.

Increased BBB permeability also allows serum proteins like fibrinogen to enter the brain, activating microglia and promoting oxidative stress. Studies have linked fibrinogen leakage to heightened neurotoxicity, suggesting that barrier dysfunction not only permits harmful molecules to enter but also prolongs neural inflammation. The presence of albumin in cerebrospinal fluid (CSF) further indicates BBB compromise, as albumin is typically restricted to the bloodstream.

Pericytes, which regulate vascular stability and immune cell trafficking, have also been implicated. Their loss or dysfunction may exacerbate BBB permeability, increasing CNS exposure to peripheral immune cells and worsening neuroinflammation and edema.

Neurological Patterns

Neurological symptoms in CAR T-cell therapy range from mild cognitive disturbances to severe encephalopathy. Patients frequently experience transient confusion, disorientation, and memory deficits, often with a fluctuating pattern of mental status changes. Some report altered time perception or difficulty processing complex information, suggesting disruptions in higher-order cognitive networks. In some cases, these cognitive disturbances persist beyond the acute phase, raising concerns about long-term neurocognitive effects.

Motor dysfunction varies widely. Some patients exhibit mild impairments such as fine motor slowing, while others develop pronounced abnormalities, including tremors, dystonia, or seizures. Myoclonus, characterized by sudden muscle jerks, has been reported in severe cases. These motor disturbances suggest dysfunction in both cortical and subcortical regions, indicating widespread neural network disruption. Patients with preexisting neurological conditions appear to be at higher risk for exacerbated motor symptoms.

Language disturbances, though less common, can be striking. Some patients develop expressive aphasia, struggling to articulate words despite intact comprehension, while others experience global aphasia, affecting both speech production and understanding. In rare cases, mutism occurs, often alongside broader neurological deterioration. These deficits may resolve as neurotoxicity subsides, though recovery varies, particularly in older patients or those with prolonged symptoms.

Typical Onset Periods

Neurotoxicity symptoms typically begin between days 1 and 10 post-infusion, peaking around days 4 to 7. This window coincides with maximal CAR T-cell expansion, though individual variability exists based on disease burden, conditioning regimens, and pharmacologic interventions. Clinical trials of tisagenlecleucel and axicabtagene ciloleucel indicate that about 80% of neurotoxicity cases present within the first week, with a smaller subset occurring later.

Early symptoms tend to be mild, including attention deficits, delayed verbal recall, or mild confusion. More severe manifestations, such as aphasia, motor dysfunction, and seizures, typically emerge between days 3 and 7, aligning with peak systemic inflammatory responses. Delayed presentations beyond day 10 are less common and may be linked to prolonged CAR T-cell persistence or concurrent complications such as infections or metabolic disturbances.

Biological Markers Of Dysfunction

Identifying biomarkers for CAR T-cell-associated neurotoxicity is crucial for early detection and intervention. Several biological markers provide insights into the underlying mechanisms driving neurological dysfunction.

Neurofilament light chain (NfL), a structural component of neuronal axons, is consistently elevated in serum and CSF, indicating axonal injury. Higher NfL levels correlate with more severe neurotoxicity, and in encephalopathic patients, these levels can remain elevated for weeks. S100 calcium-binding protein B (S100B), associated with astrocyte activation and BBB disruption, is another marker linked to severe neurological impairment.

Inflammatory markers have also been examined as predictors of neurotoxicity. High concentrations of monocyte chemoattractant protein-1 (MCP-1) in CSF reflect immune cell recruitment into the CNS. Increased levels of interleukin-1 receptor antagonist (IL-1RA) suggest a compensatory response to neuroinflammation. Fibrin degradation products in CSF indicate vascular leakage and clot formation, both contributing to cerebral edema. These biomarkers collectively enhance understanding of CAR T-cell-induced neurotoxicity and may guide future therapeutic strategies.