Neurotoxicity of Immunotherapy: Immune Checkpoint Inhibitor-Related Encephalitis vs. Immune Effector Cell-Associated Neurotoxicity Syndrome

Sep 28, 2026

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Immune checkpoint inhibitors and engineered T-cell therapies, including CAR-T and bispecific T-cell engagers, have transformed oncology care while introducing two neurologic syndromes that can appear similar at the bedside. This review contrasts immune checkpoint inhibitor-related encephalitis (irEncephalitis) and immune effector cell-associated neurotoxicity syndrome (ICANS) through differential biology, incidence, diagnostic/grading gaps, and management philosophy. It synthesizes current literature on pathophysiology, diagnostics, treatment, and clinical trial directions to support mechanism-informed, side-by-side bedside decisions.

LanguageEnglish

CategoryHealthcare

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Pages13

Reading Time33 min

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Review World J Oncol. 2026;17(1):1-13 Neurotoxicity of Immunotherapy: Immune Checkpoint Inhibitor-Related Encephalitis vs. Immune Effector Cell-Associated Neurotoxicity Syndrome Takumi Satoa, b, Kohei Chidaa, Shipra Gandhic, Kazuaki Takabea, d, e, f, g, h, i, j Abstract Immune checkpoint inhibitors and engineered T-cell therapies such as chimeric antigen receptor T-cell (CAR-T) cells and bispecific Tcell engagers (BiTEs) have revolutionized oncology care, and with them came two neurologic syndromes that look deceptively alike atthe bedside with confusion, seizures, and encephalopathy: immune checkpoint inhibitor-related encephalitis (irEncephalitis) and immune effector cell-associated neurotoxicity syndrome (ICANS) . Several differential observations between the two syndromes motivated this review: 1) although loss of immune tolerance likely drives irEncephalitis, ICANS on the other hand is dominated by cytokine-endothelialmicroglial cascades. The biology of both entities remains incompletely resolved and these lines blur in real patients, 2) irEncephalitis is uncommon in ICI recipients (∼ 0.1-1%), whereas ICANS is common after CAR-T (∼ 40% and generally lower with most T-cell engagers), 3) lack of diagnostic and grading systems, especially the absence of a dedicated irEncephalitis grading system, remains the key barrier to consistent outcomes and meaningful comparison across clinical tri- Manuscript submitted August 25, 2025, accepted October 30, 2025 Published online December 17, 2025 aBreast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA bDepartment of Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA cDepartment of Medicine, Winship Cancer Institute of Emory University, Atlanta, GA, USA dDepartment of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA eDepartment of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, NY 14263, USA fDepartment of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan gDepartment of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan hDivision of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8520, Japan iDepartment of Breast Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan jCorresponding Author: Kazuaki Takabe, Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, [USA. Email: Kazuaki.Takabe@RoswellPark.org](USA. Email: Kazuaki.Takabe@RoswellPark.org) doi: [https://doi.org/10.14740/wjon2660](https://doi.org/10.14740/wjon2660) als, and 4) management philosophies are asymmetric (restoring immune tolerance with selective immunomodulation in irEncephalitis vs. rapidly suppressing cytokine-mediated neuroinflammation with corticosteroids as well as anti-cytokine agents in ICANS) . Here wereview the existing literature on pathophysiology and current landscape of the diagnostics, management, and clinical trials to gain further structured understanding of these intriguing disorders. In doing so, we conclude that: 1) although the syndromes share similar clinical features, their pathogenesis points to distinct management algorithms based on timing of onset and response profiles, making mechanisminformed intervention central to improving outcomes; 2) early T-cell engager trials hint at molecule-dependent ICANS risk and responsiveness, warranting standardized reporting and accumulation of platform-specific data; and 3) emerging biomarkers and targets that index microglial signaling and blood-brain barrier integrity promise more precise, effective management as the field matures. In this review, we adopt a mechanism-first, side-by-side comparison that links diagno

FAQs

What are irEncephalitis and ICANS, and why are they compared in this review?

The review compares immune checkpoint inhibitor-related encephalitis (irEncephalitis) with immune effector cell-associated neurotoxicity syndrome (ICANS) because they can look deceptively alike clinically while differing in underlying biology, incidence, and management approach.

How do the incidence patterns of irEncephalitis and ICANS differ?

IrEncephalitis is described as uncommon among immune checkpoint inhibitor recipients (about 0.1%–1%), whereas ICANS is common after CAR-T therapy (about 40%), with generally lower rates for most T-cell engagers.

What key barrier prevents consistent outcomes and meaningful comparison across patients and studies?

A major barrier is the lack of dedicated diagnostic and grading systems, especially the absence of a dedicated irEncephalitis grading system, which limits consistency in outcomes and comparability.

Sep 28, 2026

Uploaded by Bulrr