ICANS, short for immune effector cell-associated neurotoxicity syndrome, is a neurological complication that can follow CAR T-cell therapy and other immune-based cancer treatments. It occurs in up to roughly a third of patients receiving these therapies, though rates vary widely depending on the specific product used.1Nature Reviews Immunology. Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy The syndrome ranges from mild word-finding difficulty and confusion to life-threatening brain swelling, and understanding it has become one of the central challenges as CAR T-cell treatments expand into more cancers and earlier lines of therapy.
What Happens Inside the Brain
ICANS unfolds through a chain of events that starts outside the nervous system entirely. When CAR T cells encounter their target, they multiply rapidly and release a flood of inflammatory signaling molecules called cytokines. That systemic cytokine surge activates the cells lining blood vessels throughout the body, including those forming the blood-brain barrier, the tightly sealed layer of cells that normally keeps most circulating substances out of the brain.2PubMed. ICANS After CAR-T Therapy: Mechanisms and Management With a Focus on Corticosteroid-Refractory ICANS
Research on patients with severe neurotoxicity has shown that this endothelial activation leads to capillary leak, clotting abnormalities, and a measurably more permeable blood-brain barrier. Once that barrier is compromised, high concentrations of cytokines that would normally stay in the bloodstream flood into the cerebrospinal fluid. One study found that interferon-gamma in particular triggered stress responses in pericytes, the support cells that wrap around brain capillaries, causing them to release even more inflammatory signals and worsening the vascular disruption.3PubMed Central. Endothelial Activation and Blood-Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells Patients who went on to develop the worst neurotoxicity already had higher markers of endothelial activation before treatment even began, suggesting that some brains are primed for trouble from the start.4PubMed Central. Endothelial Activation and Blood-Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells
More recent work has added another layer to the picture: innate immune cells, particularly monocytes and other myeloid cells, appear to infiltrate the central nervous system during ICANS. In laboratory models, depleting monocytes from the equation dramatically reduced the inflammatory signal, pointing to these cells as active participants in neuroinflammation rather than mere bystanders.5Blood. Imaging Activated Innate Immune Myeloid Cells in Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) Following CAR T-Cell Therapy Among the specific cytokines driving the process, IL-6, IL-15, IL-1, and GM-CSF have emerged as the most consistently implicated.6PubMed Central. Cytokines in CAR T Cell-Associated Neurotoxicity Cytokine profiling of patients who developed ICANS showed that IL-6 levels, for instance, were roughly nine times higher by day three after infusion compared to patients who did not develop neurotoxicity.7PubMed Central. ICANS risk model in CD19 CAR-T therapy: insights from serum and CSF cytokine profiling
How Different CAR-T Products Compare
Not all CAR T-cell products carry the same neurotoxicity risk, and the differences are substantial. The key design variable is the costimulatory domain built into the CAR construct, essentially the molecular “gas pedal” that determines how aggressively the engineered T cells activate. Products using the CD28 costimulatory domain tend to produce faster, more intense T-cell expansion and correspondingly higher ICANS rates. Products using the 4-1BB domain ramp up more gradually and cause less neurotoxicity overall.
A systematic comparison across all FDA-approved CAR-T therapies found that axicabtagene ciloleucel (axi-cel) and brexucabtagene autoleucel (brexu-cel), both CD28-based and targeting CD19, had the highest ICANS burden. In clinical trials, any-grade ICANS with axi-cel reached 64% to 78%, with severe cases (grade 3 or higher) in roughly a third of patients. Real-world data showed somewhat lower but still substantial rates. By contrast, the 4-1BB-based CD19 products lisocabtagene maraleucel (liso-cel) and tisagenlecleucel (tisa-cel) had considerably lower rates, with tisa-cel showing the lowest CD19 ICANS rates overall at 13% to 40% in trials.8Clinical Lymphoma Myeloma and Leukemia. Neurotoxicity Across All FDA-Approved CAR-T Therapies: Systematic Comparison of Pivotal Trial and Real-World Data A meta-analysis confirmed this pattern, finding that severe ICANS risk was about 2.7 times higher with CD28-based products than with 4-1BB-based products.9Clinical Lymphoma Myeloma and Leukemia. Corticosteroids With or Without Interleukin 6-Directed Therapy for the Management of Immune Effector Cell–Associated Neurotoxicity Syndrome: A Meta-Analysis
BCMA-directed products, which target a different protein found on myeloma cells rather than lymphoma or leukemia cells, tend to produce even less classic ICANS. Idecabtagene vicleucel (ide-cel) showed about 18% to 19% any-grade ICANS with severe cases in only 2% to 7%. Ciltacabtagene autoleucel (cilta-cel) had similar overall rates but introduced a different concern: a delayed neurotoxicity syndrome that could appear weeks after infusion, including movement disorders resembling parkinsonism, cranial nerve problems, and other neurological complications distinct from the early ICANS picture.10Clinical Lymphoma Myeloma and Leukemia. Neurotoxicity Across All FDA-Approved CAR-T Therapies: Systematic Comparison of Pivotal Trial and Real-World Data Meta-analysis found that CD19-targeting products carried about 4.6 times the odds of high-grade ICANS compared with BCMA-targeting products.11Clinical Lymphoma Myeloma and Leukemia. Neurotoxicity Across All FDA-Approved CAR-T Therapies: Systematic Comparison of Pivotal Trial and Real-World Data
Who Is at Higher Risk
Several patient-level and disease-level factors influence whether someone will develop ICANS and how severe it will be. Higher disease burden before treatment is one of the strongest predictors. In one study, patients who developed ICANS had tumor volumes more than double those of patients who did not, along with significantly elevated pre-infusion LDH levels and D-dimer, a marker of abnormal clotting activity.12Bone Marrow Transplantation. ICANS risk model in CD19 CAR-T therapy: insights from serum and CSF cytokine profiling
Efforts to predict severe ICANS early are gaining traction. A machine-learning model found that serum ferritin on day three after infusion was the single most predictive variable for grade 3 or higher ICANS. Patients with elevated ferritin at that time point had more than five times the odds of developing severe neurotoxicity. Other useful early markers included platelet count, patient age, IL-6 levels, and C-reactive protein, all measured within the first few days.13Journal of Clinical Oncology. Early prediction of severe ICANS after standard-of-care CD19 CAR T-cell therapy using gradient-boosted classification trees Neurofilament light chain, a blood protein released when nerve fibers are damaged, has also shown promise as a very early biomarker. Patients with elevated levels even before CAR T-cell infusion, suggesting pre-existing subclinical nerve damage, had roughly four times the odds of developing moderate-to-severe ICANS.14PubMed Central. Neurofilament light chain levels as an early predictive biomarker of neurotoxicity after CAR T-cell therapy
How ICANS Is Recognized and Assessed
ICANS typically appears within the first week or two after CAR T-cell infusion, often emerging as cytokine release syndrome (CRS), the systemic inflammatory reaction, is beginning to resolve. The earliest symptoms are frequently subtle: difficulty finding words, changes in handwriting, mild confusion, or a general sense of “not being right.” This can progress to more overt disorientation, difficulty speaking, tremors, or, in severe cases, seizures and depressed consciousness.
The standard bedside assessment uses a tool called the ICE score, which evaluates orientation, ability to name objects, ability to write a sentence, ability to count backward, and ability to follow commands. It was developed as part of the 2019 ASTCT consensus grading system intended to standardize how clinicians rate ICANS severity across different treatment centers and clinical trials.15PubMed Central. Immunotherapy-associated dysgraphia as an early neurocognitive manifestation of immune effector cell-associated neurotoxicity syndrome: clinical characteristics, mechanistic insights, and assessment challenges However, the ICE score has recognized limitations. Research into writing abnormalities during ICANS found that patients display a diverse spectrum of dysgraphia, from mild spatial disorganization to near-illegible scrawl, that the ICE score’s simple pass/fail writing task does not adequately capture.16PubMed Central. Immunotherapy-associated dysgraphia as an early neurocognitive manifestation of immune effector cell-associated neurotoxicity syndrome: clinical characteristics, mechanistic insights, and assessment challenges
When ICANS is suspected or confirmed, additional workup typically includes EEG monitoring and brain imaging. EEGs in ICANS patients show diffuse slowing in nearly all cases, with roughly 40% exhibiting a distinctive triphasic wave pattern often associated with metabolic encephalopathy. A smaller subset develop focal abnormalities or patterns on the borderline between seizure and non-seizure activity, and clinical seizures occur in a minority of patients.17PubMed Central. EEG findings in CAR T-cell-associated neurotoxicity: Clinical and radiological correlations Brain MRI findings in a study of children and young adults with ICANS showed abnormalities in about 36% of those imaged, most commonly involving the deep white matter in a bilateral, symmetric pattern. Higher ICANS grade was strongly associated with the likelihood of MRI abnormalities.18PubMed Central. Neuroimaging Findings in Children and Young Adults With Neurotoxicity After CAR T-Cell Therapy for B-Cell Malignancies
Treatment
Corticosteroids remain the backbone of ICANS management. Dexamethasone is the most commonly used because it crosses the blood-brain barrier effectively, though methylprednisolone is also recommended by FDA-approved product labels for severe cases.19Blood. How I treat refractory CRS and ICANS after CAR T-cell therapy The rationale is straightforward: dampening the inflammatory cascade in the brain to limit further damage. However, optimal dosing and duration have not been firmly established, and there is an inherent tension in giving immunosuppressive steroids to patients whose anti-cancer treatment depends on immune cell activity.20Journal of Allergy and Clinical Immunology. Cytokine release syndrome and neurotoxicity following CAR T-cell therapy for hematologic malignancies
A meaningful fraction of patients do not respond adequately to steroids, and this is where management gets more complicated. Tocilizumab, the IL-6 blocker that is a standard treatment for CRS, has limited efficacy for ICANS, likely because the large antibody molecule does not easily cross the blood-brain barrier. For steroid-refractory cases, anakinra, which blocks IL-1 signaling, has gained traction. At least one center has adopted it as their standard approach for steroid-refractory ICANS based on animal data showing IL-1’s central role in driving neurotoxicity.21Journal for ImmunoTherapy of Cancer. Single-center experience using anakinra for steroid-refractory immune effector cell-associated neurotoxicity syndrome (ICANS) Broader strategies targeting IL-1, including receptor antagonists, monoclonal antibodies, and approaches that trap or block IL-1 production, are being studied for their ability to reduce toxicity without undermining the CAR T cells’ cancer-killing function.22PubMed Central. A Systematic Review on the Dual Role of Interleukin-1 in CAR T-Cell Therapy: Enhancer and Mitigator
Can ICANS Be Prevented
Prevention trials have focused on giving anakinra prophylactically, starting it before or alongside CAR T-cell infusion rather than waiting for symptoms. In a phase 2 trial of patients receiving CD19-directed CAR-T therapy for lymphoma, prophylactic anakinra reduced severe ICANS to about 10%. Among the subset who received CD28-based products (which normally carry the highest risk), the severe ICANS rate was roughly 11%, a substantial reduction compared to historical rates of 28% to 34%.23PubMed Central. Anti-CD19 CAR T cell therapy and prophylactic anakinra in relapsed or refractory lymphoma: phase 2 trial interim results The final results from a second cohort confirmed these findings, with 10% severe ICANS and an encouraging best overall response rate of 83% by day 100, suggesting that the prophylactic strategy did not blunt the treatment’s anti-cancer effectiveness.24Blood. A Phase II Trial of Prophylactic Anakinra to Prevent Neurotoxicity in Patients Receiving Anti-CD19 CAR T-Cell Therapy for Relapsed or Refractory Lymphoma: Final Results from Cohort 2
These results are promising but come from relatively small, single-arm studies, so whether prophylactic anakinra becomes standard of care will depend on larger randomized trials. The concept of prophylaxis also intersects with product selection: choosing a 4-1BB-based construct over a CD28-based one already dramatically lowers ICANS risk. In practice, the choice of CAR-T product depends on many factors beyond toxicity, including the specific cancer type, disease biology, and availability. But when two products are equally appropriate from an efficacy standpoint, neurotoxicity profiles increasingly factor into shared decision-making between oncologists and patients.
Long-Term Cognitive Outlook
One of the most reassuring findings to emerge from the growing body of ICANS research is that cognitive impairment, even after moderate or severe episodes, tends to resolve. A study tracking cognitive recovery in the first six months after CAR-T therapy found no strong evidence of significant cognitive decline in patients who had experienced ICANS compared with those who had not. Most ICANS-related cognitive impairment resolved within the first three months, with only a small effect on one test of spatial reasoning persisting at six months.25PubMed. Cognitive Recovery Following Immune Effector Cell-Associated Neurotoxicity Syndrome in the First 6 Months after Chimeric Antigen Receptor T-Cell Therapy A separate study looking at longer-term quality of life found that neither CRS nor ICANS predicted lasting differences in cognitive function or overall symptom burden.26PubMed. Long-Term Quality of Life, Cognitive Function, and Symptom Burden Among Chimeric Antigen Receptor T-Cell Recipients and Associated Cytokine Release Syndrome and Neurotoxicity
That said, a systematic review noted that while most acute deficits resolve within one to two weeks, a subset of patients do continue to self-report persistent difficulties in the weeks and months that follow.27Journal of Autoimmunity. Cognition following chimeric antigen receptor T-cell therapy: A systematic review The challenge is that these patients are also recovering from aggressive cancer treatment, prior chemotherapy, and often the physical and psychological toll of their disease, making it difficult to disentangle what is ICANS-related and what is not. Still, for anyone weighing the risks of CAR-T therapy, the message that ICANS-related cognitive effects are usually temporary is important context.
ICANS Beyond CAR-T
Although ICANS is most closely associated with CAR T-cell therapy, it is not unique to it. Bispecific T-cell engagers, a different class of immunotherapy that redirects the patient’s existing T cells to attack cancer cells, can trigger the same neurotoxicity pattern. Blinatumomab, one of the first bispecific antibodies approved for B-cell acute lymphoblastic leukemia, lists neurotoxicity and CRS as its two major adverse events.28PubMed Central. All about blinatumomab: the bispecific T cell engager immunotherapy for B cell acute lymphoblastic leukemia Newer bispecific antibodies approved for lymphoma and myeloma carry similar warnings, though their ICANS rates are generally lower than those seen with CAR-T products. The underlying mechanism is the same: massive T-cell activation, cytokine release, and downstream brain effects.
Immune checkpoint inhibitors, another major category of cancer immunotherapy, can also cause brain inflammation, but through a fundamentally different mechanism. Rather than an acute cytokine storm, checkpoint-inhibitor-related encephalitis involves a misdirected autoimmune attack, and it is managed differently, with selective immunomodulation rather than the rapid cytokine suppression approach used for ICANS. The absence of a standardized grading system for checkpoint-inhibitor encephalitis, unlike the ASTCT consensus grading for ICANS, has made meaningful comparisons across treatment types difficult.29PubMed Central. Neurotoxicity of Immunotherapy: Immune Checkpoint Inhibitor-Related Encephalitis vs. Immune Effector Cell-Associated Neurotoxicity Syndrome
The Financial Side of Severe Neurotoxicity
ICANS is not only a medical problem but a healthcare cost driver. CAR T-cell therapy already carries a high baseline price, and the hospitalization required to manage severe toxicity adds substantially to the bill. In patients receiving ide-cel for multiple myeloma, estimated median costs of managing CRS and neurotoxicity ranged from about $17,000 for mild CRS alone to over $180,000 when grade 3 or higher events occurred, with most of that cost coming from standard inpatient hospitalization and ICU stays.30Blood. Healthcare Resource Utilization and Economic Burden of Cytokine Release Syndrome and Neurotoxicity in Patients with Relapsed and Refractory Multiple Myeloma (RRMM) Receiving Idecabtagene Vicleucel in Earlier-Line Settings in the KarMMa-3 Clinical Trial ICU admissions were dramatically more common among patients with severe toxicity, nearly 44% compared to less than 1% for those with mild events, and total hospital stays ran about 10 days longer.31Blood. Healthcare Resource Utilization and Economic Burden of Cytokine Release Syndrome and Neurotoxicity in Patients with Relapsed and Refractory Multiple Myeloma (RRMM) Receiving Idecabtagene Vicleucel in Earlier-Line Settings in the KarMMa-3 Clinical Trial
These cost differences strengthen the case for prevention and early intervention. If prophylactic strategies like anakinra can reduce the proportion of patients reaching grade 3 or higher toxicity, the downstream savings in ICU days and extended hospitalization could be significant, quite apart from the obvious benefit of sparing patients a harrowing neurological episode. As CAR-T therapy moves into earlier treatment lines and the number of eligible patients grows, the economic burden of ICANS management will only become more relevant to healthcare systems deciding how to allocate resources.