Published: 6 March 2025

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Immune effector cell-associated neurotoxicity syndrome (ICANS)

Published: 6 March 2025
Prescriber Update 46(1): 15–16
March 2025

The Columvi (glofitamab) data sheet was recently updated with information on the risk of immune effector cell-associated neurotoxicity syndrome (ICANS). This article provides an overview of ICANS.

What is ICANS?

Immune effector cell-associated neurotoxicity syndrome (ICANS) is a disorder involving the central nervous system occurring a median of 4–5 days following the use of any immunotherapy that activates or engages T-cells and/or other immune effector cells.^1-3

The underlying mechanism of ICANS is not fully understood. However, cytokines, myeloid cells, T-cells and disruption of the blood brain barrier may all play a role.⁴

ICANS frequently occurs concurrently with or shortly after cytokine release syndrome (CRS), but can also occur on its own.^4,5

Risk factors for ICANS include high disease burden, older age and patients with high-grade CRS. The risk also differs depending on each specific immunotherapy product.^2,5

Signs and symptoms of ICANS

Signs and symptoms of ICANS are initially vague and can be variable.⁵ They can be progressive and include aphasia (difficulty with language or speech), altered level of consciousness, cognitive impairment, motor weakness, seizures and cerebral oedema.¹

Non-neurologic symptoms may also be present including hepatic failure, severe hypertension, infection and electrolyte abnormalities.¹

The features of ICANS overlap with other encephalopathies. However, on examination, a key characteristic of ICANS is an alert patient who is mute.^1,5

Immunotherapies associated with ICANS

Chimeric antigen receptor (CAR) T-cell therapies are most commonly associated with ICANS. The incidence of ICANS appears to be highest for CD19-targeting CAR T-cell therapies, particularly those that have CD28-containing CAR T-cell constructs (eg, axicabtagene ciloleucel, brexucabtagene autoleucel).^2,3

T-cell engaging therapies are also associated with ICANS, but the frequency and pattern is less well characterised than with CD19-targeting CAR T-cell therapies. T-cell engaging therapies include CD3 bispecific medicines (eg, blinatumomab, epcoritamab, glofitamab).³

Management of ICANS

Management of ICANS depends on severity. Supportive care and corticosteroids are the mainstays of treatment.⁵

ICANS is usually self-limiting with symptoms lasting between 5 and 17 days. In very rare cases, malignant cerebral oedema may develop, which may be fatal.⁶

References

1. Lee DW, Santomasso BD, Locke FL, et al. 2019. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biology of Blood and Marrow Transplantion 25(4): 625-38. DOI: 10.1016/j.bbmt.2018.12.758 (accessed 10 January 2025).
2. Maus MV, Alexander S, Bishop MR, et al. 2020. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune effector cell-related adverse events. Journal for Immunotherapy of Cancer 8(2): e001511. DOI: 10.1136/jitc-2020-001511 (accessed 10 January 2025).
3. Dietrich JF, Frigault MJ. 2024. Immune effector cell-associated neurotoxicity syndrome (ICANS). In: UpToDate 22 November 2024. URL: www.uptodate.com/contents/immune-effector-cell-associated-neurotoxicity-syndrome-icans (accessed 10 January 2025).
4. Sterner RC, Sterner RM. 2022. Immune effector cell associated neurotoxicity syndrome in chimeric antigen receptor-T cell therapy. Frontiers in Immunology 13: 879608. DOI: 10.3389/fimmu.2022.879608 (accessed 10 January 2025).
5. Rees JH. 2022. Management of immune effector cell-associated neurotoxicity syndrome (ICANS). In: EBMT/EHA CAR-T Cell Handbook. Editors: N Kröger et al. Publisher: Springer International Publishing. p 141-145. DOI: 10.1007/978-3-030-94353-0_27 (accessed 10 January 2025).
6. Santomasso BD, Nastoupil LJ, Adkins S, et al. 2021. Management of immune-related adverse events in patients treated with chimeric antigen receptor T-cell therapy: ASCO guideline. Journal of Clinical Oncology 39(35): 3978-92. DOI: 10.1200/jco.21.01992 (accessed 10 January 2025).