Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)
Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)
Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) is a potentially life-threatening neurotoxicity that commonly occurs as a complication of immune effector cell therapies, particularly chimeric antigen receptor (CAR) T-cell therapy used for hematological malignancies. It manifests as a spectrum of neurological symptoms caused by immune-mediated inflammation affecting the central nervous system (CNS).
Pathophysiology
- ICANS is thought to result from a combination of blood-brain barrier (BBB) disruption, cytokine release, and infiltration of immune cells (T cells and myeloid cells) into the CNS.
- Elevated pro-inflammatory cytokines such as IL-1, IL-6, and GM-CSF contribute to neuroinflammation and BBB permeability.
- Animal models show increased BBB permeability, brain edema, and immune cell infiltration correlating with neurological symptoms.
- GM-CSF neutralization in models reduces neurotoxicity, suggesting cytokine-targeted therapies may mitigate ICANS.
- The exact mechanisms remain incompletely understood, but T cell activation and myeloid cell involvement are central.
Clinical Presentation
- Symptoms typically develop a median of 4–5 days after CAR T-cell infusion but can appear up to several weeks later.
- Early signs include mild tremor, headache, confusion, and attention deficits.
- Progression can involve aphasia (language difficulties), altered consciousness, cognitive impairment, seizures, motor weakness, and in severe cases, cerebral edema and coma.
- Non-neurologic symptoms such as hepatic failure, hypertension, and electrolyte disturbances may also be present.
- ICANS often occurs concurrently with or shortly after cytokine release syndrome (CRS), but can also occur independently.
Risk Factors
- High tumor burden
- Older age
- Severe or high-grade CRS
- Preexisting neurological dysfunction
- Elevated lactate dehydrogenase (LDH) levels
Diagnosis
- Primarily clinical, based on neurological examination and symptom assessment.
- Use of grading scales such as the Immune Effector Cell-Associated Encephalopathy (ICE) score to assess severity (grades 1–4).
- Neuroimaging (MRI) may show signs of BBB disruption or edema but can be normal.
- Laboratory tests may reveal elevated inflammatory markers and cytokines.
- Differential diagnosis includes infections, metabolic encephalopathies, and other causes of neurological symptoms.
Management
- Supportive care is essential, including seizure prophylaxis and management of cerebral edema.
- Corticosteroids are the mainstay of treatment to reduce inflammation, though optimal dosing and timing are not standardized.
- Cytokine blockade (e.g., IL-6 receptor antagonists) may be used, especially if CRS is present.
- Experimental approaches targeting GM-CSF and other cytokines are under investigation.
- Close neurological monitoring during and after CAR T-cell therapy is critical.
Prognosis
- Most cases are reversible with prompt recognition and treatment.
- Severe ICANS can cause lasting neurological deficits or death if untreated.
- Ongoing research aims to improve prevention and management strategies.
Summary Table
| Aspect | Details |
|---|---|
| Definition | Neurotoxicity syndrome associated with immune effector cell therapies (e.g., CAR T-cell therapy) |
| Onset | Median 4–5 days post-infusion, up to weeks later |
| Pathophysiology | BBB disruption, cytokine release (IL-1, IL-6, GM-CSF), immune cell infiltration |
| Clinical Features | Confusion, aphasia, tremor, seizures, altered consciousness, cerebral edema |
| Risk Factors | High tumor burden, older age, severe CRS, preexisting neurologic issues |
| Diagnosis | Clinical exam, ICE score grading, neuroimaging, labs |
| Treatment | Supportive care, corticosteroids, cytokine blockade, seizure management |
| Prognosis | Usually reversible; severe cases can be fatal |
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References
- Gust J, et al. Immune Effector Cell Associated Neurotoxicity Syndrome in Chimeric Antigen Receptor T-Cell Therapy. Front Immunol. 2022;13:944584.
https://doi.org/10.3389/fimmu.2022.944584
PMC Article - Lee DW, Santomasso BD, Locke FL, et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019;25(4):625-638.
https://doi.org/10.1016/j.bbmt.2018.12.758 - Medical News Today. ICANS: Symptoms, causes, grading, and treatment. 2024.
https://www.medicalnewstoday.com/articles/icans - Medsafe NZ. Immune effector cell-associated neurotoxicity syndrome (ICANS). Prescriber Update. 2025 Mar;46(1):15-16.
https://www.medsafe.govt.nz/profs/PUArticles/March2025/Immune-effector-cell-associated-neurotoxicity-syndrome.html - Santomasso BD, et al. Clinical Presentation, Risk Factors, and Outcomes of Immune Effector Cell-Associated Neurotoxicity Syndrome. J Clin Oncol. 2022;40(11):1174-1184.
https://doi.org/10.1200/JCO.21.02134 - Radiopaedia. Immune effector cell-associated neurotoxicity syndrome (ICANS).
https://radiopaedia.org/articles/immune-effector-cell-associated-neurotoxicity-syndrome-icans
ICANS is a serious neurotoxic complication of CAR T-cell and other immune effector cell therapies, characterized by a range of neurological symptoms due to immune-mediated CNS inflammation. Early recognition and management are essential to improve outcomes.
