ICANS and Its Neuroinflammatory Roots in CAR T-Cell Treatments

Chimeric antigen receptor (CAR) T-cell therapy has transformed cancer treatment, particularly for hematologic malignancies. However, it comes with serious side effects, including immune effector cell-associated neurotoxicity syndrome (ICANS). This condition can cause neurological symptoms ranging from mild confusion to life-threatening cerebral edema, making it a critical concern in patient management.

Understanding ICANS requires examining the mechanisms driving its development and progression.

Immunological Basis

ICANS in CAR T-cell therapy stems from the immune system’s response to engineered T cells. Once infused, CAR T cells rapidly expand and activate, targeting malignant cells while also triggering immune interactions that can affect the central nervous system (CNS). This process involves CAR T-cell activation, systemic inflammation, and blood-brain barrier (BBB) permeability, all contributing to neurotoxicity.

CAR T cells rely on synthetic receptors to recognize tumor-associated antigens, such as CD19 in B-cell malignancies. Upon antigen engagement, they proliferate and release inflammatory mediators, including interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukins like IL-6 and IL-1β. While these cytokines enhance immune function, excessive activity disrupts immune homeostasis, leading to widespread inflammation.

The BBB regulates molecule passage between the bloodstream and CNS, maintaining neural integrity. However, inflammatory cytokines like IL-6 and TNF-α can weaken it by altering tight junction proteins and increasing endothelial permeability. This allows immune cells and inflammatory mediators to enter the CNS, triggering neuroinflammation and ICANS symptoms.

Direct immune cell infiltration into the CNS has been observed in ICANS patients. Postmortem analyses and cerebrospinal fluid (CSF) studies reveal elevated CAR T-cell levels in the CNS, suggesting migration across a compromised BBB. This infiltration, along with increased CSF cytokine concentrations, amplifies local inflammation, exacerbating neuronal dysfunction and contributing to symptoms ranging from mild cognitive impairment to severe encephalopathy.

Neuroinflammatory Components

The neuroinflammatory landscape of ICANS involves CNS resident cells, vascular integrity, and inflammatory mediators. Once the BBB is compromised, the brain is exposed to cytokines and immune cells that disrupt neuronal function. Microglia, the CNS’s primary immune cells, shift to a pro-inflammatory state, releasing additional cytokines such as IL-1β and TNF-α. This cycle of inflammation exacerbates neuronal stress, contributing to cognitive impairments and encephalopathy.

Astrocytes, which support neuronal function, also react to heightened inflammation. This reactive gliosis involves increased glial fibrillary acidic protein (GFAP) expression and chemokine secretion, attracting peripheral immune cells. Astrocytic dysfunction disrupts neurotransmitter regulation, particularly glutamate homeostasis, leading to excitotoxicity and neuronal damage. This imbalance is linked to severe ICANS symptoms, including seizures and impaired consciousness.

Endothelial activation within cerebral vasculature further amplifies neuroinflammation. Elevated adhesion molecules like intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) facilitate immune cell infiltration into the CNS. Combined with increased vascular permeability, this leads to perivascular inflammation, a hallmark of ICANS. Endothelial dysfunction contributes to cerebral edema, one of ICANS’s most severe complications.

Differences From Other Neurological Events

ICANS presents with symptoms resembling other neurological conditions, but its mechanisms and trajectory set it apart. Unlike neurodegenerative disorders such as Alzheimer’s disease, which progress over years, ICANS develops rapidly, often within days of CAR T-cell infusion. This acute onset aligns more closely with conditions like posterior reversible encephalopathy syndrome (PRES) or acute toxic encephalopathies, where brain function is suddenly disrupted due to systemic disturbances.

Despite symptomatic overlap with PRES—such as altered mental status, seizures, and cerebral edema—ICANS follows a distinct pathophysiology. PRES is primarily linked to endothelial dysfunction from hypertension or cytotoxic drug exposure, whereas ICANS arises independently of blood pressure fluctuations. Neuroimaging shows that while both conditions can present with vasogenic edema, ICANS more often involves diffuse cortical regions rather than the posterior-predominant patterns seen in PRES.

Seizures in ICANS also differ from those in epilepsy. Unlike epilepsy, where seizures originate from intrinsic neuronal hyperexcitability, ICANS-related seizures are often nonconvulsive and stem from widespread cortical dysfunction. EEG monitoring reveals diffuse slowing and generalized rhythmic delta activity, patterns indicative of global encephalopathy rather than focal seizure initiation. This suggests ICANS is a systemic disruption affecting brain function rather than a primary neurological disorder.

Markers of Neurotoxicity

Identifying reliable ICANS markers is crucial for early detection and intervention. One of the most consistent indicators is encephalopathy, manifesting as cognitive decline from mild confusion to profound unresponsiveness. Clinicians use the Immune Effector Cell-Associated Encephalopathy (ICE) score to assess orientation, naming ability, command following, writing, and attention. A declining ICE score signals worsening neurological dysfunction and informs ICANS severity grading.

CSF analysis provides additional insights. ICANS patients often exhibit elevated neurofilament light chain (NfL) levels, a biomarker of axonal injury correlated with disease severity. Increased CSF protein concentration and pleocytosis reflect BBB disruption and immune cell infiltration, distinguishing ICANS from other neurological complications.

Neuroimaging helps identify structural and functional changes. MRI may reveal cerebral edema or subtle cortical abnormalities, while diffusion-weighted imaging (DWI) highlights cytotoxic injury. Functional imaging, such as positron emission tomography (PET), shows altered metabolic activity in affected regions, reinforcing the idea that ICANS involves widespread neuronal dysfunction rather than focal pathology.

Relationship With Cytokine Release Syndrome

ICANS and cytokine release syndrome (CRS) frequently co-occur in CAR T-cell therapy, suggesting a mechanistic link. CRS typically precedes ICANS, with systemic inflammation escalating before neurological symptoms emerge. Elevated IL-6, IL-1β, and IFN-γ levels in CRS correlate with ICANS onset and severity, reinforcing the role of widespread immune activation in neurotoxicity.

The severity of CRS influences ICANS risk. Patients with high-grade CRS, characterized by fever, hypotension, and organ dysfunction, are more likely to develop severe neurotoxicity. Endothelial dysfunction in CRS exacerbates BBB permeability, facilitating inflammatory mediator entry into the CNS. Elevated serum angiopoietin-2, a marker of endothelial activation, is associated with both CRS severity and ICANS development. Addressing CRS early may help mitigate subsequent neurological complications.

Common Patterns in Pediatric and Adult Populations

Differences in immune system dynamics and neurological resilience contribute to variations in ICANS presentation between pediatric and adult patients. While both groups experience neurotoxicity, distinct patterns emerge. Pediatric ICANS often presents with more pronounced encephalopathy, including lethargy and irritability, whereas adults are more likely to develop expressive aphasia and cognitive disorientation. These differences may stem from variations in blood-brain barrier integrity and neuroimmune regulation.

ICANS duration and recovery also vary by age. Pediatric patients tend to have a more rapid onset but recover more quickly, likely due to greater neuroplasticity. In contrast, adults, particularly those with preexisting neurological conditions, may experience prolonged or more severe ICANS episodes. Older age is a risk factor for high-grade neurotoxicity, with increased rates of cerebral edema and persistent cognitive deficits in elderly patients. These differences underscore the need for age-specific management strategies tailored to neuroinflammatory responses and recovery trajectories.