ICANS vs CRS: Mechanistic Origins and Clinical Insights

Immune effector cell-associated neurotoxicity syndrome (ICANS) and cytokine release syndrome (CRS) are major complications of immune-based cancer therapies, particularly chimeric antigen receptor (CAR) T-cell therapy. While both result from excessive immune activation, CRS primarily affects systemic inflammation, whereas ICANS involves neurological dysfunction. Understanding their distinctions is crucial for optimizing treatment and improving patient outcomes.

A deeper look at their mechanisms, inflammatory pathways, clinical symptoms, and diagnostic markers helps differentiate these syndromes and guide appropriate interventions.

Mechanistic Origins

ICANS and CRS arise from the profound immune activation triggered by CAR T-cell therapy. Both conditions stem from the engagement of genetically modified T cells with target antigens, but their downstream effects differ due to variations in cellular interactions, signaling pathways, and tissue-specific responses. CAR T-cell therapy relies on synthetic receptors that recognize tumor-associated antigens, leading to robust T-cell activation and cytokine secretion, including interleukin-6 (IL-6), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α). This cytokine surge amplifies T-cell cytotoxicity and recruits myeloid-derived cells such as monocytes and macrophages. The extent of immune activation determines whether the response remains controlled or escalates into systemic inflammation, as seen in CRS, or breaches the blood-brain barrier, contributing to ICANS.

Endothelial cells play a central role in modulating both syndromes. Excess cytokines induce endothelial activation, increasing vascular permeability and releasing von Willebrand factor (vWF) and angiopoietin-2, which disrupt vascular integrity. In CRS, this exacerbates systemic inflammation, while in ICANS, it facilitates the entry of inflammatory mediators and immune cells into the central nervous system (CNS). Blood-brain barrier breakdown allows neurotoxic cytokines and immune cells to infiltrate the CNS, driving neurological symptoms.

Inflammatory Cascade

The inflammatory cascade in ICANS and CRS is driven by a surge of pro-inflammatory cytokines and immune cell interactions that amplify systemic and localized immune responses. CAR T cells, upon recognizing tumor-associated antigens, rapidly release cytokines such as IL-6, IFN-γ, and TNF-α. These molecules act as immune amplifiers, triggering a feedback loop that recruits monocytes and macrophages, further escalating cytokine production. The persistence of this cytokine surge dictates whether the inflammatory response remains controlled or progresses to pathological levels.

Endothelial cells contribute significantly to this process. High IL-6 and TNF-α levels induce endothelial activation, increasing adhesion molecule expression and promoting leukocyte adhesion and transmigration. This intensifies inflammation and leads to vascular instability. In CRS, this manifests as capillary leak syndrome and hypotension, while in ICANS, it facilitates blood-brain barrier breakdown, allowing neurotoxic cytokines and immune cells into the CNS.

Severe cases of CRS and ICANS often involve activation of the coagulation cascade. Elevated D-dimer and fibrinogen levels indicate a pro-thrombotic state driven by endothelial dysfunction and systemic inflammation. This hypercoagulable environment exacerbates tissue damage and contributes to organ dysfunction, particularly in severe CRS where multi-organ failure can occur. The interplay between inflammation and coagulation underscores the systemic impact of these syndromes, highlighting the need for early intervention.

Clinical Presentations

The clinical manifestations of ICANS and CRS vary in severity and presentation. CRS typically emerges within the first few days after CAR T-cell infusion, presenting with flu-like symptoms such as fever, fatigue, and myalgias. As it progresses, hypotension, tachycardia, and hypoxia may develop, often requiring vasopressor support and supplemental oxygen. Severe cases can involve multi-organ dysfunction, including acute kidney injury, hepatic transaminitis, and disseminated intravascular coagulation. Early intervention with IL-6 inhibitors like tocilizumab can prevent deterioration.

ICANS primarily affects neurological function and often arises later, peaking around one to two weeks post-CAR T-cell therapy. Early signs include word-finding difficulties, confusion, and impaired handwriting, which can progress to cognitive dysfunction, expressive aphasia, and altered mental status. Unlike CRS, which affects hemodynamic stability, ICANS can lead to seizures, cerebral edema, and coma. Motor deficits such as rigidity or tremors further distinguish ICANS. Electroencephalographic abnormalities, including diffuse slowing and epileptiform discharges, indicate widespread cortical involvement.

ICANS symptoms can fluctuate, making diagnosis challenging. Frequent neurological assessments using standardized grading scales, such as the American Society for Transplantation and Cellular Therapy (ASTCT) criteria, help categorize severity. Unlike CRS, which often responds rapidly to cytokine blockade, ICANS management relies more on corticosteroids, as IL-6 inhibitors alone are insufficient for reversing neurological symptoms. The differential response to treatment highlights the distinct pathophysiology of these syndromes and the importance of tailored therapeutic strategies.

Neurological Factors

The neurological disruptions in ICANS stem from vascular permeability, excitotoxicity, and direct cellular dysfunction within the CNS. Blood-brain barrier breakdown allows neurotoxic molecules to accumulate in cerebrospinal fluid, exposing neurons and glial cells to inflammatory mediators. This alters synaptic transmission and contributes to widespread cortical dysfunction. Functional imaging studies have shown diffuse cerebral edema in severe cases, correlating with encephalopathy and seizures. Subclinical epileptiform activity on electroencephalography suggests neuronal hyperexcitability plays a central role in ICANS.

Cognitive impairments often involve executive function, memory, and language processing, with some patients exhibiting transient expressive aphasia or dysgraphia. These symptoms reflect dysfunction in the dominant hemisphere’s cortical networks, particularly in the frontal and temporal lobes. The fluctuating nature of these deficits indicates a reversible disruption in neuronal signaling rather than permanent structural damage. Magnetic resonance imaging (MRI) findings are typically nonspecific, but in severe cases, T2 hyperintensities in white matter suggest a role for demyelination in prolonged or severe presentations.

Severity Assessment

ICANS and CRS severity is classified using grading systems that assess symptom progression, medical intervention needs, and risk of long-term complications. These scales guide treatment decisions, helping clinicians determine when to escalate supportive care or initiate targeted therapies.

CRS severity grading is based on fever persistence, hemodynamic instability, and respiratory compromise. Lower grades (1–2) involve fever with mild hypotension responsive to fluids, while higher grades (3–4) include severe hypotension requiring vasopressors, hypoxia necessitating high-flow oxygen or mechanical ventilation, and multi-organ dysfunction. The ASTCT grading criteria standardize CRS assessment, guiding the use of IL-6 inhibitors such as tocilizumab and corticosteroids in severe cases.

ICANS severity is determined by cognitive impairment, motor dysfunction, and the presence of seizures or cerebral edema. The Immune Effector Cell-Associated Encephalopathy (ICE) score quantifies neurological deterioration by evaluating orientation, speech, and motor coordination. Mild ICANS may present as subtle confusion or expressive aphasia, while severe cases involve profound encephalopathy, seizures, or brainstem dysfunction, necessitating intensive neurocritical care. The potential for rapid neurologic decompensation underscores the need for continuous monitoring, particularly in high-risk patients with early signs of blood-brain barrier disruption.

Laboratory Indicators

Biomarkers play a significant role in differentiating ICANS from CRS and predicting disease progression. While both syndromes share overlapping inflammatory markers, distinct laboratory findings help delineate their pathophysiology and guide treatment.

In CRS, elevated C-reactive protein (CRP) and ferritin levels reflect systemic inflammation, with extreme elevations correlating with severe disease. IL-6, a central mediator of CRS, is often markedly increased and serves as a pharmacodynamic marker for tocilizumab efficacy. Elevated D-dimer and fibrinogen levels indicate a hypercoagulable state, contributing to thrombotic complications.

In contrast, ICANS is associated with elevated cerebrospinal fluid (CSF) protein and an increased CSF-to-serum albumin ratio, indicative of blood-brain barrier dysfunction. Neurofilament light chain, a marker of neuronal injury, reflects axonal damage and persistent neuroinflammation. Elevated serum IL-1 receptor antagonist and granulocyte-macrophage colony-stimulating factor (GM-CSF) further differentiate ICANS from CRS, highlighting distinct inflammatory pathways.