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Neurotoxicity—CAR T-cell therapy: what the neurologist needs to know
  1. Lorna Neill1,2,
  2. Jeremy Rees3,
  3. Claire Roddie2
  1. 1University College London Hospitals NHS Foundation Trust, London, UK
  2. 2University College London, London, UK
  3. 3Neurology, National Hospital for Neurology and Neurosurgery, London, UK
  1. Correspondence to Dr Claire Roddie, University College London, London WC1E 6BT, UK; c.roddie{at}


Chimeric antigen receptor (CAR) T-cell therapy is one of the most innovative therapies for haematological malignancies to emerge in a generation. Clinical studies have shown that a single dose of CAR T-cells can deliver durable clinical remissions for some patients with B-cell cancers where conventional therapies have failed.

A significant complication of CAR therapy is the immune effector cell-associated neurotoxicity syndrome (ICANS). This syndrome presents a continuum from mild tremor to cerebral oedema and in a minority of cases, death. Management of ICANS is mainly supportive, with a focus on seizure prevention and attenuation of the immune system, often using corticosteroids. Parallel investigation to exclude other central nervous system pathologies (infection, disease progression) is critical. In this review, we discuss current paradigms around CAR T-cell therapy, with a focus on appropriate investigation and management of ICANS.

  • Tumours
  • Toxicology
  • Neuropathology
  • Neurooncology
  • Epilepsy
  • Paraneoplastic syndrome
  • Clinical neurology
  • Haematology
  • Oncology

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A chimeric antigen receptor (CAR) is an artificial T-cell receptor, which grafts the specificity of a monoclonal antibody on to a T-cell, ‘redirecting’ it to recognise and kill tumour cells (figure 1). The CAR consists of a single-chain variable fragment, which binds to the tumour antigen, fused to a T-cell transmembrane domain and a costimulatory signalling endodomain, which drives activation and proliferation of CAR T-cells upon antigen recognition.1 CAR receptors recognise cell surface tumour targets, and the best-described CAR target is the B-cell protein CD19, expressed at high density on B-cell cancers.

Figure 1

A CAR T-cell.

CART, chimeric antigen receptor.

Clinical trials have shown CAR T-cells can eliminate certain cancers in patients where chemotherapy has failed; a significant proportion of patients, particularly children with B-acute lymphoblastic leukaemia appear to be cured of their cancer by a single dose.2 Furthermore, unlike chemotherapy, CAR T-cells form part of the immune system, potentially giving the patient ‘immunity’ against their cancer, preventing relapse. CAR T-cells have shown greatest activity in haematological malignancies and represent the biggest breakthrough in this field for a generation.

Autologous CAR T-cells are manufactured directly from patient T-cells and represent a personalised medicine. The pathway from referral to infusion can take 6–8 weeks and is outlined in figure 2. The first step is to ‘harvest’ T-cells from the patient in a process called leukapheresis. Briefly, T-cells are separated from whole blood via a peripheral or central catheter according to a density gradient in a blood cell separator machine. During this time, white blood cells are diverted into a collection bag while other blood components circulate back to the patient.3 This harvest is then transferred to the manufacturing laboratory where the CAR cassette is introduced to the cells via gene transfer, using lentiviral or retroviral vector technology. The CAR T-cells are expanded in vitro for several days before formulation, cryopreservation and quality assessment. Once the CAR T-cell product has passed stringent testing for safety, phenotype and potency, it can be scheduled for patient administration.4

Figure 2

Process of harvesting and manufacturing CAR T-cells.

CART, chimeric antigen receptor.

Several pivotal clinical trials have shown impressive, durable responses in relapsed/refractory B-acute lymphoblastic leukaemia2 and adult high-grade B-cell lymphoma.5 6 Based on these trial data, two CD19-directed CAR T-cell products have successfully undergone approvals via the European Medicines Agency and cost-effectiveness analysis via the National Institute for Health and Care Excellence, and are currently licensed for use in UK patients on the National Health Service (NHS) at designated CAR T-cell centres.

Tisagenlecleucel (Kymriah) is licensed for use in both relapsed/refractory paediatric B-acute lymphoblastic leukaemia and relapsed/refractory adult high-grade B-cell lymphoma, and axicabtagene ciloleucel (Yescarta) is licensed for relapsed/refractory adult high-grade B-cell lymphoma.7 8 A third CD19 CAR T-cell product, lisocabtagene maraleucel, has performed well in clinical studies and is likely to achieve European Medicines Agency and UK approvals for use in relapsed/refractory adult high-grade B-cell lymphoma.9

CAR T-cell therapy has a unique side effect profile, reflecting the mode of action of CAR T-cells and is distinct from that of conventional chemotherapy, radiotherapy or other immune therapies such as checkpoint inhibitors. Tumour target binding by CAR T-cells results in T-cell activation, expansion, and cytotoxicity with subsequent recruitment of the innate immune system. Clinically, this process is often characterised by high fevers, and in some cases by haemodynamic instability and hypoxia (leading to multi-organ failure in severe cases) and is referred to as cytokine release syndrome (CRS). This syndrome is managed supportively with close involvement of critical care physicians, as inotropic, renal and respiratory support can be required. Central to the pathophysiology of cytokine release syndrome is excessive release of interleukin-6 (IL-6), which mediates the persistent fever. Tocilizumab, an anti-IL-6 receptor antibody developed for use in inflammatory arthropathies, has shown excellent efficacy in the management of cytokine release syndrome, where a single dose of 8 mg/kg can lead to rapid and complete defervescence.10


Another common, challenging side effect associated with CAR T-cell therapy is immune effector cell-associated neurotoxicity syndrome (ICANS), the cause of which is not yet fully understood. Its clinical presentation is a continuum from mild tremor to cerebral oedema, and in a minority of cases, death.11 Most cases resolve spontaneously with supportive care and early intervention with corticosteroid therapy. As the use of CAR T-cell therapy expands, it becomes increasingly important to educate physicians and healthcare staff to recognise the early signs of ICANS, to identify high-risk patient populations and optimally investigate and manage this potentially fatal condition.

Clinical studies of CD19 CAR T-cells suggest that onset of ICANS could be expected around day 5 following CAR T-cell infusion.5 6 12 13 Some cases present early alongside concurrent cytokine release syndrome, but more commonly, it develops several days after cytokine release syndrome has resolved.14 Delayed onset of ICANS (>3 weeks post-infusion) is not uncommon, occurring in up to 10% of some patient cohorts14 and is of particular concern as patients may be at home when it occurs. For this reason, patients and carers must be educated about delayed-onset ICANS, so that they can be vigilant for symptoms and communicate promptly with their CAR T-cell centre should this occur. Several groups report that severe cytokine release syndrome is strongly associated with severe ICANS,12 13 but occasional cases of severe ICANS occur with only mild or no preceding cytokine release syndrome.13 15

The incidence and phenotype of ICANS varies across distinct CAR products and disease indications. For instance, all-grade ICANS across clinical studies of tisagenlecleucel (Tisagen), axicabtagene ciloleucel (Axi-Cel) and lisocabtagene maraleucel (Liso-Cel) for relapsed/refractory adult high-grade B-cell lymphoma is reported in 21%,5 64%6 and 25%9 of patients, respectively. More significantly, the incidence of grade ≥3 ICANS occurs in 12%5, 31%6 and 15%9 of patients, respectively, indicating that severe ICANS is more strongly associated with specific products and permits the identification of high-risk populations.

The symptoms of ICANS are variable and can initially be vague. Some patients experience mild encephalopathy, tremor and confusion, whereas other more severe presentations include agitation, seizures and cerebral oedema. The classical presentation of ICANS is often described as an encephalopathy with preserved alertness.12

Difficulties with language are an early, prominent feature of ICANS.14 16 Expressive dysphasia develops frequently and can manifest as word-finding difficulties, verbal perseveration, paraphasic errors, hesitant speech and deterioration in handwriting.13 16 Milder presentations can progress into global aphasia with expressive and receptive components. In this setting, the patient is alert but mute. In an analysis of ICANS associated with CAR therapy in a phase 1 trial for 53 adults with B-acute lymphoblastic leukaemia, expressive dysphasia was the first symptom of ICANS in 86% of the most severely affected patients (19/22).13 Language deficits occur at a variable frequency between clinical trials and real-world cohorts, ranging from 3% to 50% of all treated patients.5 6 12 15 Compared to other symptoms, language difficulties are very specific for ICANS and should prompt clinicians to monitor language closely following cell infusion. The pathogenesis underlying this phenomenon is poorly understood. There appears to be no clear correlation with imaging, no overt association with seizure activity, nor with cerebrospinal fluid (CSF) anomalies. Some groups have reported CD19 expression in pericytes in the brain, but why this would preferentially affect language centres is not clear. Alternative hypotheses include the suggestion that the cytokine/chemokine receptor distribution is different across anatomically distinct areas of the brain, rendering specific regions more sensitive to the cytokine/chemokine flux associated with CAR T-cell activation, or that disruption of the blood–brain barrier may cause a spreading wave of cortical depolarisation, leading to these focal symptoms.17 This is an area of active research interest.

Other common but non-specific symptoms include tremor,5 6 confusion and headache.5 16 ICANS is often associated with fluctuating neurological deficits such that symptoms can resolve, then reappear.15 In a study of 100 consecutive patients,17 the most common neurological symptom was generalised encephalopathy, seen in 57 cases, often waxing and waning, with or without accompanying confusion, impulsivity and emotional lability. Twenty-one cases had a depressed level of awareness, ranging from mild somnolence to significant lethargy. Fifteen cases had agitated delirium, with impulsivity and aggression. In contrast, only four patients were abulic.17

Seizures can also be a feature, with an incidence of between 8%2 and 30%.13 Prophylactic antiepileptic medications do not always protect patients from developing seizures during ICANS.13 Non-convulsive status epilepticus may also occur, although less frequently.13 14

The most devastating consequence of ICANS is the development of cerebral oedema and/or death from cerebral toxicity. This phenomenon was first clearly recognised in the ROCKET II study,11 when five patients died from cerebral oedema which was thought to be directly related to CD19 CAR T-cells. Subsequent reviews suggest that fatal ICANS observed in the ROCKET II study was a unique phenomenon,11 rather than being a feature of all CD19-directed CAR T-cells. Reassuringly, fatal ICANS has not been a significant feature in other major CD19 CAR T-cell studies.


To date, the pathophysiology of ICANS is not fully understood. However, there is an emerging consensus that it is mediated by an increase in inflammatory cytokines leading to disruption and activation of the vascular endothelium, a consumptive coagulopathy and a breakdown of the blood–brain barrier.12 13 18 This hypothesis is based on observations from cohorts of patients with ICANS in several large CD19 CAR T-cell clinical studies.

There is an emerging narrative around risk factors for ICANS. It is clear that high disease burden at the point of CAR T-cell infusion equates to a higher risk of ICANS.12 13 Further, pharmacokinetic studies indicate that greater and earlier CAR T-cell expansion in vivo correlates with a higher risk of developing ICANS.6 12 13 Other factors that have been linked to a higher incidence of severe ICANS include higher CAR T-cell doses,12 13; pre-existing neurological conditions12; low platelet count (<50 × 109/L)13 15; factors predisposing to capillary leak and loss of vascular integrity (low serum albumin; increased patient weight)12; and high-grade cytokine release syndrome.2 12 17 Certainly, high fever (≥38.9°C) within 36 hours of CAR infusion associated with haemodynamic instability predicts for a more severe presentation of ICANS with high sensitivity.12

Some studies have reported that fludarabine and cyclophosphamide preconditioning administered prior to CAR T-cell therapy may be associated with a higher risk of ICANS.12 19 It is unclear whether this is simply a fludarabine effect, as the association with fludarabine and leukoencephalopathy is well described, or whether lymphodepletion simply potentiates CAR T-cell expansion which in itself can lead to a higher incidence of ICANS.6 12 13

There have been attempts to identify serum markers to predict the development of severe ICANS. Emerging evidence correlates higher peak blood concentrations of C-reactive protein, ferritin and a range of cytokines (IL-6, interferon gamma (IFNγ), tumour necrosis factor alpha (TNFα), interleukin-10 (IL-10) and interleukin-5 (IL-5)) with a more severe ICANS phenotype.12 13 A study of 133 patients following CAR T-cell therapy indicated that early serum peak concentrations of IL-6, monocyte chemoattractant protein-1 (MCP-1) and a body temperature of ≥38.9°C within 36 hours of CAR T-cell infusion predicted patients who would develop grade 4 neurotoxicity (as per CTCAE version 4.03) with 100% sensitivity and 94% specificity.12 This suggests that systemic inflammation plays a significant role in the development of ICANS.

Endothelial activation is likely to play a major role in the development of ICANS. The angiopoietin (ANG)—tyrosine kinase with immunoglobulin-like and EGF-like domains 2 (TIE-2) axis—controls the balance between endothelial activation and quiescence. The ratio between ANG-1, which promotes endothelial quiescence, and ANG-2, which promotes activation and microvascular permeability, both of which competitively bind to the TIE-2 receptor, is higher in patients with severe ICANS.12 13 19 Elevations in plasma levels of von Willebrand factor develop in patients with high-grade ICANS and support the hypothesis of endothelial activation as contributory to the pathophysiology.12 Certainly, endothelial activation and capillary leak together with the use of lymphodepletion chemotherapy probably contribute to the blood–brain barrier disruption that occurs in ICANS.

Several investigators have reported that a high prothrombin time, high D-dimers and low fibrinogen with concurrent thrombocytopenia (suggesting a consumptive coagulopathic process) correlate with more severe cytokine release syndrome and ICANS.12 15 19

CSF in patients with ICANS often shows a mild leucocytosis and a raised CSF protein,12 13 suggesting increased blood–brain barrier permeability and disruption.12 Indeed, raised CSF protein concentrations correlate with severity of neurotoxicity.13 Another study compared inflammatory cytokines (IFNy, TNFα, IL-6) in serum and CSF of patients pre- and post- ICANS and found that CSF cytokine levels were significantly higher than would be expected within the CNS and were comparable to serum levels. This again suggests blood–brain barrier breakdown permitting systemic cytokine permeation into the CNS.

CAR T-cells traffic to the CNS and are commonly found in the CSF, but studies indicate that CAR T-cell concentration in the CSF does not appear to correlate with the likelihood of developing ICANS or indeed the severity of ICANS.12 13 In one report, postmortem examination of two patients who died of severe ICANS identified a significant CAR T-cell infiltrate in the involved brain parenchyma and CSF of both patients, suggesting direct CAR T-cell mediated brain toxicity.12 By contrast, a different group reporting on brain tissue changes in cases of severe ICANS found severe oedema and astrocyte injury, but without significant CAR T-cell brain infiltration.17 We clearly need a deeper understanding of the pathophysiology of ICANS, particularly pertaining to the more severe, and on occasion, irreversible cases.

ICANS can develop following CAR T-cell therapy for diffuse large B-cell lymphoma, transformed follicular lymphoma, primary mediastinal B-cell lymphoma and B-acute lymphoblastic leukaemia.20 It has also been described in clinical trials of CAR T-cells for non-CD19 targets such as B-cell maturation antigen for multiple myeloma and in CD20 for adult high-grade B-cell lymphoma,21 22 which suggests that direct targeting of CD19 is unlikely to be the unifying driver of the syndrome. Interestingly, neurotoxic events may occur in the context of other non-CAR immunotherapies for blood cancers. Blinatumomab, a bispecific anti-CD3/CD19 T-cell engager used in B-acute lymphoblastic leukaemia, is associated with all-grade and ≥ grade 3 neurotoxicity in 52% and 13% of patients respectively, and preventative strategies such as pulsed dexamethasone before cycle 1 are now commonplace.23


All patients with suspected ICANS should have a thorough neurological examination (including fundoscopy to exclude papilloedema) and a review by a clinical neurologist.

Patients should undergo neuroimaging with MRI, or with CT if MRI is not available. Standard pre and post gadolinium T1w, T2w, FLAIR, DWI and susceptibility-weighted sequences should be requested, the latter being sensitive to intracranial haemorrhage. Often, patients with significant neurotoxicity have normal neuroimaging. In most cases, CT imaging will be normal but serves to exclude other pathologies such as acute ischaemic stroke or a haemorrhagic event. Occasional patients have cerebral oedema.17

MRI appearances can often be normal, even in patients with severe grade 3–4 ICANS.17 However, several studies have reported white matter hyperintensities on T2/FLAIR images,12 13 sometimes involving the bilateral thalami, external capsule or corpus callosum.13 Other MRI changes include vasogenic oedema, microhaemorrhages and leptomeningeal enhancement.12

CSF and opening pressure should be assessed if there are no contraindications and samples should be sent for microscopy, cytology, virology and biochemistry. Procuring CSF can be challenging due to the practical difficulty of lumbar puncture in patients with severe ICANS and is clearly contraindicated in those with raised intracranial pressure and those with refractory thrombocytopenia/coagulopathy.12

Patients with suspected ICANS, even low grade 1/2, as well as those with seizures or suspected non-convulsive status epilepticus, should have an electroencephalogram (EEG). This can show a pattern of diffuse slowing,12 frontal intermittent rhythmic delta activity13 or general periodic discharges with triphasic morphology.24 Several other non-epileptiform EEG abnormalities may occur, including generalised asynchronous slow activity and focal slowing. Patients with focal EEG abnormalities often have focal neurological symptoms including aphasia. A few patients have spike-wave and other epileptiform discharges.17 In one case series, EEG changes did not respond to up-titration of antiepileptic drugs but did respond to dexamethasone.24 Ongoing or intermittent EEGs should be performed where ongoing abnormality is suspected and antiepileptic medication/corticosteroids titrated to EEG activity to gain control.25


In patients at high risk for ICANS, patients should receive seizure prophylaxis with an antiepileptic agent such as levetiracetam at a dose of 750 mg 12 hourly from the start of the CAR T-cell infusion.14 Where there is a new neurological deficit, it is critical to investigate thoroughly all cases to exclude non-CAR causes of neurotoxicity (eg, CNS infection; drug toxicity; relapsed disease; intracerebral haemorrhage). These patients are highly immunosuppressed and greatly susceptible to atypical CNS infection.

All patients should be proactively monitored for ICANS twice daily assessing for subtle changes in neurocognition.14 A consensus document published by an expert committee on behalf of the American Society of Transplant and Cell Therapy (ASTCT) recommends a 10-point immune effector cell-associated encephalopathy (ICE) score (table 1)16 as part of the ICANS grading system (table 2).16 The ICE score evaluates patient attention, writing, and language. This score is then integrated into an overall assessment of neurological function incorporating seizure activity, change in conscious level, motor anomalies and elevation in intracerebral pressure/cerebral oedema to give an overall ICANS grade.16

Table 1

Immune effector cell-associated encephalopathy (ICE) score16

Table 2

American Society for Transplantation and Cellular Therapy (ASTCT) ICANS consensus grading for adults16

Management of ICANs is based on the severity of the score and the concurrence of cytokine release syndrome (table 3). If there is concurrent cytokine release syndrome, then tocilizumab can be given at a suggested dose of 8 mg/kg.14 It should be noted that there is some concern that prophylactic or early use of tocilizumab for cytokine release syndrome (and prevention of cytokine release syndrome) does not prevent and may even potentially increase the incidence of neurotoxicity, as raised levels of cytokines such as IL-6 may occur after its use.13 26

Table 3

Approach to management of ICANS14 16 25 27

For grade 1 ICANS, management is supportive. For grade ≥2 ICANS, corticosteroid therapy should be considered. Suggested doses include 10–20 mg intravenous dexamethasone every 6 hours for grades 2–3 ICANS and 1 g intravenous methylprednisolone for at least 3 days for grade 4 ICANS. Depending on the grade of ICANS, patients should receive dexamethasone or methylprednisolone until improvement of their symptoms (table 3).14 27

Patients with ≥ grade 3 ICANS should ideally be managed in an intensive care setting and patients with reduced consciousness may need intubation. For seizure activity, benzodiazepines are likely to be required for initial control followed by loading with levetiracetam/other antiepileptic medications.

There have been some attempts to assess the efficacy of steroid-sparing agents. Siltuximab distinguishes itself from tocilizumab in that it binds IL-6 directly rather than the IL-6 receptor. In theory, this could control symptoms of concurrent cytokine release syndrome/ICANS without creating a surge of IL-6 from occupation of all IL-6 receptor sites, potentially protecting the CNS from high levels of this cytokine. Siltuximab is also a smaller molecule, so is in theory more likely to permeate the blood–brain barrier and potentially reduce IL-6 concentration within the CNS.28 Siltuximab was used during initial trials of Axi-Cel,29 30 but there are no directly comparative studies with tocilizumab and very sparse published data on its efficacy in cytokine release syndrome and ICANS.

Anakinra is an IL-1 receptor antagonist and is commonly used in the management of haemophagocytic lymphohistiocytosis, a hyperinflammatory condition that has some cross over with cytokine release syndrome. Anakinra has been shown to prevent ICANS in animal models31 and there is a case report showing clinical benefit in cytokine release syndrome that was refractory to tocilizumab.28 To date, there is limited evidence to support its widespread use and clinical trials are urgently required.

Intravenous immunoglobulin has been suggested as an immune-modulating strategy for ICANS, but there is limited data. In one report of a small cohort of patients receiving intravenous immunoglobulin plus corticosteroids compared to corticosteroid alone, there was no clear benefit in terms of time to resolution of ICANS.32 Again, this would benefit from exploration in a well-designed clinical study.

Other approaches to the management of ICANS have been directed at controlling the potency of the CAR itself. Several CAR constructs have been designed with ‘suicide switches’, inbuilt mechanisms designed to turn off the CAR in the event of severe toxicity.33 34 Other strategies include ‘tunable CARs’, where CAR activity can be switched off in the event of toxicity using small molecules35 and use of the tyrosine kinase inhibitor dasatinib which has been shown to induce an ‘off’ state for infused CAR T-cells, giving protection against fatal cytokine release syndrome in a mouse model.36 All of these approaches need further exploration to maximise their potential.


CAR T-cell therapy has transformed treatment options for patients with relapsed/refractory B cell malignancies. The use of CAR T-cells is growing exponentially in the UK due to access through the NHS CAR programme and due to experimental studies exploring earlier use of CAR T-cells in first-line salvage and as an alternative to autologous stem cell transplantation. Furthermore, CAR T-cells are being investigated for other haematological malignancies such as multiple myeloma, acute myeloid leukaemia and even for solid tumours, for example, glioblastoma. The need to develop CAR T-cell products with good expansion and persistence to deliver robust clinical responses must be tempered with the potential risks of heightened toxicity associated with rapidly expanding CAR T-cell populations in vivo.

There is growing evidence that ICANS is associated with cytokine release, vascular permeability, endothelial activation and blood–brain barrier breakdown, but the underlying mechanism driving the syndrome is not fully understood. It is important to identify patients at high risk of developing ICANS so that they can be appropriately monitored for its emergence and swiftly managed in an attempt to prevent escalation to more severe phenotypes. Factors associated with a higher risk of ≥grade 3 ICANS include patients with higher disease burden, patients with low platelet counts, patients with consumptive coagulopathy and patients who develop an early and severe cytokine release syndrome.

Several studies are exploring the use of early and prophylactic corticosteroids and to date have suggested no adverse effect on CAR T-cell expansion or persistence.37 38 However, the longer-term effects on outcome and survival are unknown. The use of high-dose corticosteroid is not without risk in this immunosuppressed patient population.

Not all patients with perceived ICANS will respond to corticosteroids. In this setting, it is critical to perform ongoing MRI evaluation and regular EEG to exclude the emergence of seizure activity. Furthermore, a careful assessment of alternative causes of neurological toxicity should be performed regularly, given the multiplicity of opportunistic infections whose symptoms can mimic those of ICANS.

If ICANS is refractory to corticosteroids, then anakinra or siltuximab can be considered. However, experience with these agents is limited to case studies and preclinical assessment, so there is no clear evidence for potential efficacy or information on dosing.2830 Several groups are exploring the use of anakinra in a prophylactic setting to help prevent ICANS,39 but work is needed to strengthen the evidence for all of these options for use in steroid refractory cases.

Awareness and proactive management of ICANS is needed in order to optimally manage patients. CAR T-cell therapy is currently performed in specialist centres, but the number of centres is growing and patients who have received CAR T-cell therapy may present to their local centres with late complications. Although ICANS typically occurs during the initial few days post infusion, some patients develop symptoms in the third or fourth week post infusion. This creates a need for not just haematologists, but emergency medicine physicians, general physicians, neurologists and intensivists to be aware of this condition and its management.

CAR T-cell therapy represents a revolutionary exciting new treatment for haematological malignancies and is a rapidly growing field. Our knowledge of the toxicities associated with these therapies is growing, but there remains a lack of evidence on which to base clinical practice. Education of physicians who will be involved in the treatment of these complex patients is key to safe management and use of CAR T-cells in the clinic.

Key points

  • Immune effector cell-associated neurotoxicity syndrome (ICANS) is a serious complication of CAR T-cell therapy, which can be life-threatening

  • Patients undergoing CAR T-cell therapy need daily assessments in specialist centres while undergoing their treatment to monitor for development of ICANS, via the immune effector cell-associated encephalopathy (ICE) scoring system

  • Once established, depending on the grading, other causes such as infection or haemorrhage are excluded; treatment is based on corticosteroid therapy as well as other supportive therapy such as antiepileptic medication and lowering intracranial pressure

  • Novel treatments such as anakinra, siltuximab and intravenous immunoglobulin need further exploration to assess their efficacy in neurotoxicity

  • Involvement and education of all healthcare professionals about CAR T-cell therapy and its associated toxicities is vital to safely manage this complex group of patients


We are grateful to Josephine Dand for producing the images to accompany this review article.



  • Contributors NL, JR and CR authors contributed to the final version of the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests CR has received speaker fees from Novartis, Kite Gilead and Celgene. LN has been supported by Celgene to attend an academic conference.

  • Patient consent for publication Not required.

  • Provenance and peer review Commissioned. Externally peer reviewed by David McKee, Manchester, UK.

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