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

Abstract

Immune checkpoint inhibitors and engineered T-cell therapies such as chimeric antigen receptor T-cell (CAR-T) cells and bispecific T-cell engagers (BiTEs) have revolutionized oncology care, and with them came two neurologic syndromes that look deceptively alike at the 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-endothelial-microglial 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 trials, 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 we review 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 mechanism-informed 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 diagnosis, management, and evolution to bedside decisions, with the aim of enabling precise diagnosis and management for oncologists, neurologists, and trialists operating in the rapidly expanding era of T-cell-based immunotherapy.