REVIEW
Pract Neurol: first published as 10.1136/practneurol-2020-002550 on 5 June 2020. Downloaded from http://pn.bmj.com/ on June 5, 2020 at Rutgers University. Protected by copyright.
1
University College London
Hospitals NHS Foundation Trust,
London, UK
2
University College London,
London, UK
3
Neurology, National Hospital for
Neurology and Neurosurgery,
London, UK
Correspondence to
Dr Claire Roddie, University
College London, London WC1E
6BT, UK; c.roddie@ucl.ac.uk
Accepted 22 April 2020
© Author(s) (or their
employer(s)) 2020. No
commercial re-use. See rights
and permissions. Published by
BMJ.
To cite: Neill L, Rees J,
Roddie C. Pract Neurol Epub
ahead of print: [please
include Day Month Year].
doi: 10.1136/
practneurol-2020-002550
Neurotoxicity—CAR T-cell therapy:
what the neurologist needs to know
Lorna Neill ,1,2 Jeremy Rees,3 Claire Roddie2
ABSTRACT
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.
CAR T-CELL THERAPY
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 con-
sists 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.
Clinical trials have shown CAR T-cells can
eliminate certain cancers in patients where
chemotherapy has failed; a significant pro-
portion of patients, particularly children
with B-acute lymphoblastic leukaemia
appear to be cured of their cancer by
a single dose.2 Furthermore, unlike che-
motherapy, CAR T-cells form part of the
immune system, potentially giving the
Neill L, et al. Pract Neurol 2020;0:1–9. doi:10.1136/practneurol-2020-002550
patient ‘immunity’ against their cancer, pre-
venting relapse. CAR T-cells have shown
greatest activity in haematological malig-
nancies and represent the biggest break-
through in this field for a generation.
Autologous CAR T-cells are manufac-
tured 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 leukapher-
esis. 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
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 paedia-
tric B-acute lymphoblastic leukaemia and
relapsed/refractory adult high-grade
B-cell lymphoma, and axicabtagene cilo-
leucel (Yescarta) is licensed for relapsed/
1
 REVIEW
Figure 1 A CAR T-cell.
CART, chimeric antigen receptor.
Figure 2 Process of harvesting and manufacturing CAR T-cells.
CART, chimeric antigen receptor.
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,
2 Neill L, et al. Pract Neurol 2020;0:1–9. doi:10.1136/practneurol-2020-002550
Pract Neurol: first published as 10.1136/practneurol-2020-002550 on 5 June 2020. Downloaded from http://pn.bmj.com/ on June 5, 2020 at Rutgers University. Protected by copyright.
radiotherapy or other immune therapies such as check-
point 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 suppor-
tively 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
IMMUNE EFFECTOR CELL-ASSOCIATED
NEUROTOXICITY SYNDROME
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 cere-
bral 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 increas-
ingly 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 fol-
lowing 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 commu-
nicate 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 tisa-
genlecleucel (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 initi-
ally be vague. Some patients experience mild encepha-
lopathy, tremor and confusion, whereas other more
severe presentations include agitation, seizures and cer-
ebral 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 difficul-
ties, 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, expres-
sive 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 clini-
cians to monitor language closely following cell infu-
sion. The pathogenesis underlying this phenomenon is
poorly understood. There appears to be no clear corre-
lation with imaging, no overt association with seizure
activity, nor with cerebrospinal fluid (CSF) anomalies.
Some groups have reported CD19 expression in peri-
cytes in the brain, but why this would preferentially
affect language centres is not clear. Alternative hypoth-
eses include the suggestion that the cytokine/chemo-
kine receptor distribution is different across
anatomically distinct areas of the brain, rendering spe-
cific regions more sensitive to the cytokine/chemokine
flux associated with CAR T-cell activation, or that dis-
ruption 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 com-
mon neurological symptom was generalised encepha-
lopathy, seen in 57 cases, often waxing and waning,
with or without accompanying confusion, impulsivity
and emotional lability. Twenty-one cases had
Neill L, et al. Pract Neurol 2020;0:1–9. doi:10.1136/practneurol-2020-002550
REVIEW
Pract Neurol: first published as 10.1136/practneurol-2020-002550 on 5 June 2020. Downloaded from http://pn.bmj.com/ on June 5, 2020 at Rutgers University. Protected by copyright.
a depressed level of awareness, ranging from mild som-
nolence to significant lethargy. Fifteen cases had agi-
tated 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 devel-
oping 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.
CAUSES AND RISK FACTORS FOR DEVELOPMENT
OF NEUROTOXICTY
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 cyto-
kines leading to disruption and activation of the vascu-
lar 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 expan-
sion in vivo correlates with a higher risk of develop-
ing 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 neurolo-
gical 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
3
 REVIEW
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 compe-
titively 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 chemother-
apy probably contribute to the blood–brain barrier
disruption that occurs in ICANS.
Several investigators have reported that a high pro-
thrombin time, high D-dimers and low fibrinogen with
concurrent thrombocytopenia (suggesting a consumptive
coagulopathic process) correlate with more severe cyto-
kine release syndrome and ICANS.12 15 19
CSF in patients with ICANS often shows a mild
leucocytosis and a raised CSF protein,12 13 suggest-
ing increased blood–brain barrier permeability and
disruption.12 Indeed, raised CSF protein concentra-
tions 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 bar-
rier breakdown permitting systemic cytokine per-
meation 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
4 Neill L, et al. Pract Neurol 2020;0:1–9. doi:10.1136/practneurol-2020-002550
Pract Neurol: first published as 10.1136/practneurol-2020-002550 on 5 June 2020. Downloaded from http://pn.bmj.com/ on June 5, 2020 at Rutgers University. Protected by copyright.
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 signif-
icant 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 folli-
cular lymphoma, primary mediastinal B-cell lym-
phoma 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 strate-
gies such as pulsed dexamethasone before cycle 1 are
now commonplace.23
INVESTIGATIONS: MRI, EEG AND CSF
EXAMINATION
All patients with suspected ICANS should have
a thorough neurological examination (including fun-
doscopy 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 nor-
mal 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 hyperinten-
sities 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 electro-
encephalogram (EEG). This can show a pattern of dif-
fuse 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 asyn-
chronous 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
MANAGEMENT AND GRADING OF ICANS
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 inves-
tigate 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 sus-
ceptible 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 incor-
porating seizure activity, change in conscious level,
motor anomalies and elevation in intracerebral
Table 1 Immune effector cell-associated encephalopathy (ICE) score16
Immune effector cell-associated encephalopathy (ICE) score
• Orientation: orientation to year, month, city, hospital: 4 points
• Naming: ability to name three objects (eg, point to clock, pen,
button): 3 points
• Following commands: ability to follow simple commands (eg,
‘Show me two fingers’ or ‘Close your eyes and stick out your
tongue’): 1 point
• Writing: ability to write a standard sentence (eg, ‘Our national bird
is the bald eagle’): 1 point
• Attention: ability to count backwards from 100 by 10: 1 point
Neill L, et al. Pract Neurol 2020;0:1–9. doi:10.1136/practneurol-2020-002550
REVIEW
Pract Neurol: first published as 10.1136/practneurol-2020-002550 on 5 June 2020. Downloaded from http://pn.bmj.com/ on June 5, 2020 at Rutgers University. Protected by copyright.
pressure/cerebral oedema to give an overall ICANS
grade.16
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 syn-
drome, 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 tocilizu-
mab 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
For grade 1 ICANS, management is supportive. For
grade ≥2 ICANS, corticosteroid therapy should be
considered. Suggested doses include 10–20 mg intrave-
nous 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 dexametha-
sone 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 sei-
zure activity, benzodiazepines are likely to be required
for initial control followed by loading with levetirace-
tam/other antiepileptic medications.
There have been some attempts to assess the
efficacy of steroid-sparing agents. Siltuximab dis-
tinguishes itself from tocilizumab in that it binds
IL-6 directly rather than the IL-6 receptor. In the-
ory, this could control symptoms of concurrent
cytokine release syndrome/ICANS without creating
a surge of IL-6 from occupation of all IL-6 recep-
tor 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 tocilizu-
mab and very sparse published data on its efficacy
in cytokine release syndrome and ICANS.
Anakinra is an IL-1 receptor antagonist and is com-
monly used in the management of haemophagocytic
lymphohistiocytosis, a hyperinflammatory condition
that has some cross over with cytokine release syn-
drome. 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
5
REVIEW

Pract Neurol: first published as 10.1136/practneurol-2020-002550 on 5 June 2020. Downloaded from http://pn.bmj.com/ on June 5, 2020 at Rutgers University. Protected by copyright.
Table 2 American Society for Transplantation and Cellular Therapy (ASTCT) ICANS consensus grading for adults16
Overall ICANS grade Grade 1 Grade 2 Grade 3 Grade 4
ICE score* 7–9 3–6 0–2 0 (Patient is unarousable and unable to perform
the test)
Depressed level of Awakens Awakens Awakens only to tactile stimulus Patient is unarousable or requires vigorous or
consciousness† spontaneously to voice repetitive tactile stimuli to arouse. Stupor or
coma
Seizure N/A N/A Any clinical seizure focal or generalised Life-threatening prolonged seizure (>5 min); or
that resolves rapidly or non-convulsive repetitive clinical or electrical seizures without
seizures on EEG that resolve with return to baseline in between
intervention
Motor findings‡ N/A N/A N/A Deep focal motor weakness such as hemiparesis
or paraparesis
Elevated intracranial N/A N/A Focal/local oedema on neuroimaging§ Diffuse cerebral oedema on neuroimaging;
pressure/cerebral decerebrate or decorticate posturing; or sixth
oedema cranial nerve palsy; or papilledema; or Cushing’s
triad
ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings, raised intracranial pressure/cerebral oedema)
not attributable to any other cause; for example, a patient with an ICE score of 3 who has a generalised seizure is classified as grade 3 ICANS.
N/A indicates not applicable.
*A patient with an ICE score of 0 may be classified as grade 3 ICANS if awake with global aphasia, but a patient with an ICE score of 0 may be classified as
grade 4 ICANS if unarousable.
†Depressed level of consciousness should be attributable to no other cause (eg, no sedating medication).
‡Tremors and myoclonus associated with immune effector cell therapies may be graded according to CTCAE v5.0, but they do not influence ICANS grading.
§Intracranial haemorrhage with or without associated oedema is not considered a neurotoxicity feature and is excluded from ICANS grading. It may be graded
according to CTCAE v5.0.
CTCAE, Common Terminology Criteria for Adverse Events; EEG, electroencephalogram; ICANS, immune effector cell-associated neurotoxicity syndrome; ICE,
immune effector cell-associated encephalopathy; N/A indicates not applicable.

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 max-
imise their potential.
CONCLUSION
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 malig-
nancies such as multiple myeloma, acute myeloid
leukaemia and even for solid tumours, for example,
glioblastoma. The need to develop CAR T-cell pro-
ducts with good expansion and persistence to deli-
ver 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, endothe-
lial 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 escala-
tion 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 immuno-
suppressed patient population.
Not all patients with perceived ICANS will respond
to corticosteroids. In this setting, it is critical to perform

6 Neill L, et al. Pract Neurol 2020;0:1–9. doi:10.1136/practneurol-2020-002550


Table 3 Approach to management of ICANS14 16 25 27
ICANS grade Management
Grade 1 Consider levetiracetam as prophylaxis against
seizures (750 mg two times per day)
Avoid any medications that may cause depression of
the central nervous system
Ensure review by a specialist neurologist
Supportive care and consider swallowing assessment
Examination to exclude papilloedema by funduscopy
MR scan of brain with (CT scan of brain if MR scan of
brain is not feasible)
Consider diagnostic lumbar puncture with
measurement of opening pressure where possible,
sending samples for microscopy culture and
sensitivity, cytology, biochemistry, virology as
a minimum
Consider MR scan of spine if the patient has focal
peripheral neurological deficits
Consider electroencephalogram
Consider tocilizumab 8 mg/kg if concurrent cytokine
release syndrome
Two times per day neurocognitive assessment using
immune effector cell-associated encephalopathy
score and ICANS grading
Grade 2 Investigations and supportive care as per grade 1
Consider dexamethasone as dosed for grade 3
Consider transferring patient to intensive care unit
Grade 3 Investigations and supportive care as per grade 1
Administer dexamethasone 10–20 mg intravenously
every 6 hours or methylprednisolone equivalent until
improvement to grade 1 and then taper gradually
Management of seizures with lorazepam 0.5 mg
intravenously or other benzodiazepines as needed,
followed by loading with levetiracetam or other
antiepileptic medications as required
If there is evidence of raised intracranial pressure,
either by funduscopy (stage 1 or 2 papilloedema) and
or with cerebrospinal fluid (CSF) opening pressure
>20 mmHg, ensure urgent specialist neurology
review seek
Consider repeat neuroimaging (CT or MRI) every
2–3 days for persistent grade ≥3 ICANS
Grade 4 Investigations and supportive care as per grade 1
Transfer patient to intensive care unit and consider
mechanical ventilation for airway protection
Seizure management as per grade 3
For convulsive status epilepticus, ensure urgent
specialist neurology review Administer
methylprednisolone 1000 mg/day for 3 days, then
taper at 250 mg every 12 hours for 2 days, then
125 mg every 12 hours for 2 days, then 60 mg every
12 hours for 2 days
For management of raised intracranial pressure,
consider acetazolamide 1000 mg intravenously,
followed by 250–1000 mg intravenously every
12 hours, consideration of head of the bed elevation,
hyperventilation and hyperosmolar therapy with
mannitol, based on guidance from intensive care
specialists
ICANS, immune effector cell-associated neurotoxicity syndrome.
ongoing MRI evaluation and regular EEG to exclude
the emergence of seizure activity. Furthermore,
a careful assessment of alternative causes of neurologi-
cal toxicity should be performed regularly, given the
Neill L, et al. Pract Neurol 2020;0:1–9. doi:10.1136/practneurol-2020-002550
REVIEW
Pract Neurol: first published as 10.1136/practneurol-2020-002550 on 5 June 2020. Downloaded from http://pn.bmj.com/ on June 5, 2020 at Rutgers University. Protected by copyright.
multiplicity of opportunistic infections whose symp-
toms can mimic those of ICANS.
If ICANS is refractory to corticosteroids, then ana-
kinra or siltuximab can be considered. However, experi-
ence with these agents is limited to case studies and
preclinical assessment, so there is no clear evidence for
potential efficacy or information on dosing.28–30 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 cen-
tres, 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 malig-
nancies and is a rapidly growing field. Our knowl-
edge of the toxicities associated with these therapies
is growing, but there remains a lack of evidence on
which to base clinical practice. Education of physi-
cians 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
7
 REVIEW
Acknowledgements 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.
ORCID iD
Lorna Neill http://orcid.org/0000-0003-3108-0974
REFERENCES
1 June CH, Sadelain M. Chimeric antigen receptor therapy.
N Engl J Med 2018;379:64–73.
2 Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in
children and young adults with B−cell lymphoblastic leukemia.
N Engl J Med 2018;378:439–48.
3 Roberts ZJ, Better M, Bot A, et al. Axicabtagene ciloleucel, a
first-in-class CAR T cell therapy for aggressive NHL. Leuk
Lymphoma 2018;59:1785–96.
4 Roddie C, O’Reilly M, Dias Alves Pinto J, et al. Manufacturing
chimeric antigen receptor T cells: issues and challenges.
Cytotherapy 2019;21:327–40.
5 Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult
relapsed or refractory diffuse large B−cell lymphoma. N Engl
J Med 2019;380:45–56.
6 Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleu-
cel car T-cell therapy in refractory large B−cell lymphoma.
N Engl J Med 2017;377:2531–44.
7 FDA. YESCARTA (axicabtagene ciloleucel). FDA: 2019.
Available http://www.fda.gov/vaccines-blood-biologics/cellular-
gene-therapy-products/yescarta-axicabtagene-ciloleucel
(accessed 18 Feb 2020).
8 FDA. KYMRIAH (tisagenlecleucel). FDA. 2019. Available http://
www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-
products/kymriah-tisagenlecleucel (accessed 18 Feb 2020).
9 Abramson JS, Gordon LI, Palomba ML, et al. Updated safety and
long term clinical outcomes in TRANSCEND NHL 001, pivotal
trial of lisocabtagene maraleucel (JCAR017) in R/R aggressive
NHL. J Clin Oncol 2018;36:7505–7505.
10 Le RQ, Li L, Yuan W, et al. FDA approval summary: tocilizumab
for treatment of chimeric antigen receptor Tcell-induced severe or
life-threatening cytokine release syndrome. Oncologist
2018;23:943–7.
11 Poh A. JCAR015 in ALL: a root-cause investigation. Cancer
Discov 2018;8:4–5.
12 Gust J, Hay KA, Hanafi L-A, et al. Endothelial activation and
blood-brain barrier disruption in neurotoxicity after adoptive
immunotherapy with CD19 CAR-T cells. Cancer Discov
2017;7:1404–19.
13 Santomasso BD, Park JH, Salloum D, et al. Clinical and biolo-
gical correlates of neurotoxicity associated with CAR T-cell
therapy in patients with B−cell acute lymphoblastic leukemia.
Cancer Discov 2018;8:958–71.
14 Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen
receptor T-cell therapy - assessment and management of
toxicities. Nat Rev Clin Oncol 2018;15:47–62.
8 Neill L, et al. Pract Neurol 2020;0:1–9. doi:10.1136/practneurol-2020-002550
Pract Neurol: first published as 10.1136/practneurol-2020-002550 on 5 June 2020. Downloaded from http://pn.bmj.com/ on June 5, 2020 at Rutgers University. Protected by copyright.
15 Karschnia P, Jordan JT, Forst DA, et al. Clinical presentation,
management, and biomarkers of neurotoxicity after adoptive
immunotherapy with CAR T cells. Blood 2019;133:2212–21.
16 Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus
grading for cytokine release syndrome and neurologic toxicity
associated with immune effector cells. Biol Blood Marrow
Transplant J Am Soc Blood Marrow Transplant 2019;25:625–38.
17 Rubin DB, Danish HH, Ali AB, et al. Neurological toxicities
associated with chimeric antigen receptor T-cell therapy. Brain
J Neurol 2019;142:1334–48.
18 Brudno JN, Kochenderfer JN. Recent advances in CAR T-cell
toxicity: mechanisms, manifestations and management. Blood
Rev 2019;34:45–55.
19 Hay KA, Hanafi L-A, Li D, et al. Kinetics and biomarkers of
severe cytokine release syndrome after CD19 chimeric antigen
receptor-modified T-cell therapy. Blood 2017;130:2295–306.
20 Gauthier J, Turtle CJ. Insights into cytokine release syndrome
and neurotoxicity after CD19-specific CAR-T cell therapy. Curr
Res Transl Med 2018;66:50–2.
21 Raje NS, Berdeja JG, Lin Y, et al. bb2121 anti-BCMA CAR T-cell
therapy in patients with relapsed/refractory multiple myeloma:
updated results from a multicenter phase I study. J Clin Oncol
2018;36:8007–8007.
22 Taraseviciute A, Tkachev V, Ponce R, et al. Chimeric antigen
receptor T cell-mediated neurotoxicity in non-human primates.
Cancer Discov 2018;8:750–63.
23 Topp MS, Gökbuget N, Stein AS, et al. Safety and activity of
blinatumomab for adult patients with relapsed or refractory B
−precursor acute lymphoblastic leukaemia: a multicentre, sin-
gle-arm, phase 2 study. Lancet Oncol 2015;16:57–66.
24 Herlopian A, Dietrich J, Abramson JS, et al. EEG findings in
CAR T-cell therapy-related encephalopathy. Neurology
2018;91:227–9.
25 The University of Texas MD Anderson Cancer Center. ICE
therapy toxicity assessment and management (also known as
CARTOX) - adult. Available https://www.mdanderson.org/
documents/for-physicians/algorithms/clinical-management/clin-
management-cytokine-release-web-algorithm.pdf (accessed 1
Feb 2020).
26 Locke FL, Neelapu SS, Bartlett NL, et al. Preliminary results of
prophylactic tocilizumab after axicabtageneciloleucel (axi-cel;
KTE-C19) treatment for patients with refractory,aggressive
non-hodgkin lymphoma (NHL). Blood 2017;130:1547–1547.
27 Neelapu SS. Managing the toxicities of CAR T-cell therapy.
Hematol Oncol 2019;37:48–52.
28 Specialist Pharmacy Service. Evidence for use of siltuximab or
anakinra as second line therapies (after failure of tocilizumab)
for Cytokine Release Syndrome (CRS) following use of
Chimeric Antigen Receptor T-cell (CAR-T) therapy. 2019.
Available https://www.sps.nhs.uk/wp-content/uploads/2019/05/
SPS_Siltuximab_Anakinra_CRS_postCAR_T_FINALApr19.pdf
(accessed 1 Mar 2020).
29 Lee DW, Wayne AS, Dietz AC, et al. Updated results from Zuma-4:
a phase 1/2 study of KTE-C19 chimeric antigen receptor (CAR)
T cell therapy in pediatric and adolescent patients with relapsed/
refractory acute lymphoblastic leukemia. [Abstract]. Presented at
2017 EHA Annual Meeting 22-25 June 2017. Abstract E840.
30 Shah B, Huynh V, Sender L, et al. High rates of minimal residual
disease-negative (MRD−) complete responses (CR) in adult and
pediatric and patients with relapsed/refractory acute lympho-
blastic leukemia (R/R ALL) treated with KTE-C19 (Anti-CD19
chimeric antigen receptor [CAR] T Cells): preliminary results of
the ZUMA-3 and ZUMA-4 trials. Blood 2016;128:2803–2803.

31 Norelli M, Camisa B, Barbiera G, et al. Monocyte-derived IL-1
and IL-6 are differentially required for cytokine-release syndrome
and neurotoxicity due to CAR Tcells. Nat Med 2018;24:739–48.
32 Mokhtari S, Asquith JM, Bachmeier CA, et al. The use of intra-
venous immunoglobulin (IVIG) during severe neurotoxicity
among the recipients of chimeric antigen receptor T-cell
(CAR-T) therapy. Blood 2019;134:5627–5627.
33 Stavrou M, Philip B, Traynor-White C, et al. A
rapamycin-activated caspase 9-based suicide gene. Mol Ther
2018;26:1266–76.
34 Philip B, Kokalaki E, Mekkaoui L, et al. A highly compact
epitope-based marker/suicide gene for easier and safer T-cell
therapy. Blood 2014;124:1277–87.
35 Wu C-Y, Roybal KT, Puchner EM, et al. Remote control of
therapeutic T cells through a small molecule-gated chimeric
receptor. Science 2015;350:aab4077.
Neill L, et al. Pract Neurol 2020;0:1–9. doi:10.1136/practneurol-2020-002550
REVIEW
Pract Neurol: first published as 10.1136/practneurol-2020-002550 on 5 June 2020. Downloaded from http://pn.bmj.com/ on June 5, 2020 at Rutgers University. Protected by copyright.
36 Mestermann K, Giavridis T, Weber J, et al. The tyrosine kinase
inhibitor dasatinib acts as a pharmacologic on/off switch for
CAR T cells. Sci Transl Med 2019;11.
37 Topp M, Van Meerten TV, Houot R et al. Earlier steroid use with
axicabtagene ciloleucel (Axi-Cel) in patients with relapsed/refrac-
tory large B cell lymphoma. [Abstract]. Presented at 2019 ASH
Annual Meeting 7-10 Dec 2019. Orlando FL;Abstract 243.
38 Gardner RA, Leger KJ, Annesley C, et al. Decreased rates of severe
CRS seen with early intervention strategies for CD19 CAR-T cell
toxicity management. [Abstract]. Presented at 2016 ASH Annual
Meeting 3-6 Dec 2016. San Diego CA; Abstract 612. Blood.
39 Anakinra in preventing severe chimeric antigen receptor T-cell
related encephalopathy syndrome in patients with recurrent or
refractory large B−cell lymphoma - full text view - clinicaltrials.
gov. Available https://clinicaltrials.gov/ct2/show/NCT04205838
(accessed 18 Feb 2020).
9