Cytokine release syndrome (CRS) and neurotoxicity are common adverse events associated with chimeric antigen receptor (CAR) T cell therapies that result from the inflammatory response initiated when CAR T cells are activated by their target antigen.
The typical time to CRS is approximately 1-5 days following CAR T cell infusion. However, time to onset can be delayed and can present beyond 14 days.
- Incidence rates will vary depending on the disease and the CAR T cell product infused.
26 - Signs and symptoms of CRS can vary significantly between patients and the CAR T cell therapy products themselves. Clinical features include, but are not limited to, fevers, myalgias, malaise, and, in more severe cases, a capillary leak syndrome associated with hypoxia, hypotension, and, occasionally, prolonged cytopenias, coagulopathy, end-organ damage, and organ failure.
26,27 - These toxicities can generally be managed. However, severe cases, which can be life-threatening or fatal, require intensive medical management, including support with vasoactive pressors, mechanical ventilation, antiepileptics, and antipyretics.
1,20
Neurotoxicity refers to neurologic adverse events that can cause confusion, tremors, or difficulty with communication. It is also known as immune effector cell–associated neurotoxicity syndrome (ICANS). ICANS is hypothesized to occur when cytokines disrupt the blood-brain barrier, which can be life threatening.
- Neurotoxicity incidence varies and generally coincides with, or shortly follows the onset of, CRS.
26 - More severe symptoms can occur after CRS symptoms subside, often more than 5 days after CAR T infusion.
29 - Delayed neurotoxicity can arise 3 to 4 weeks after treatment or later.
29,30 - Symptoms of neurotoxicity can include, but are not limited to, aphasia, confusion, drowsiness, delirium, and hallucinations.
1,29 - In rare cases, bradycardia, hypertension, respiratory depression, and coma also can occur.
28 - In some patients, symptoms can progress to CAR T related encephalopathy syndrome (CRES), which can present severe symptoms. For example, patients with serious CRS (Grade ≥3) may develop reversible neurologic complications, including delirium and seizure-like activity.
29 - Neurotoxicity may even have life-threatening or fatal consequences.
28


Onset and duration times are generalized and can be longer than what is depicted. Incidence, onset, and duration of CRS and neurotoxicity varies among individual patients and CAR T products.
Onset/duration of CAR T toxicities
Some events associated with CAR T cell therapy differ from those typically seen with traditional modalities, such as stem cell transplantation, or from other immunotherapies.
- Onset: Toxicities associated with CAR T cell therapy are largely a byproduct of initial CAR T cell expansion and activation following infusion. Toxicities such as CRS, for example, usually do not continue while CAR T cells persist and disseminate in the blood.
26,29,32 However, some toxicities may have later onset, such as B cell aplasias or prolonged cytopenias, and should be managed with appropriate intervention for blood count recovery.1,26,34 - Duration: Some toxicities occur within 30 days.
33 While the lymphodepletion regimens used with CAR T cell therapy are less intensive, the low blood counts that follow conditioning chemotherapy may need to be managed in some patients.33
Associated syndromes/conditions:
- Macrophage activation syndrome (MAS) and tumor lysis syndrome have also been observed. However, these are not unique to CAR T cell therapy, and MAS is not comparable to CRS.
1,26,29 - Hypogammaglobulinemia can also drive higher rates of infection among treated patients, and off-tumor effects can occur among healthy cells that express the target antigen.
29
Risk factors for more severe toxicities include the following and should be considered when evaluating a patient for CAR T cell therapy:

- Presence of comorbidities and compromised organ function
27 - High disease burden
27 - Presence of infection at the time of CAR T cell infusion, which would preclude or delay the use of CAR T cell therapy
27 - Presence of immunodeficiency or autoimmune disease
27 - High doses of infused CAR T cells in certain patients
26
Symptom monitoring and AE management
Symptom Recognition and Timely Response Are Keys to Management33
Early recognition of symptoms and timely response are essential for appropriate management of CRS and neurotoxicity. While grading systems and management guidelines tend to be institution-specific or trial-dependent, general guidance has been proposed by several experts in CAR T cell therapy. This includes
The American Society of Transplantation and Cellular Therapy (ASTCT) has published ICANS (immune effector cell-associated neurotoxicity syndrome) consensus grading guidelines for CRS and neurotoxicities.
While there are grading systems associated with certain products, the goal of ICANS is to provide a uniform grading system for CRS and neurotoxicity associated with CAR T cell therapy for use across clinical trials and in the post-approval clinical setting.
ASTCT Consensus Grading Guidelines for CRS28
Grade 1 | Grade 2 | Grade 3 | Grade 4 | |
---|---|---|---|---|
Fevera | Temp ≥38 ℃ | Temp ≥38 ℃ | Temp ≥38 ℃ | Temp ≥38 ℃ |
With Hypotension | None | Not requiring a vasopressor | Requiring a vasopressor with or without vasopressin | Requiring multiple vasopressors (excluding vasopressin) |
And/orb Hypoxia | None | Requiring low-flow nasal cannulac or blow-by | Requiring high-flow nasal cannula,c face mask, non-rebreather mask, or Venturi mask | Requiring positive pressure (eg, CPAP, BiPAP, intubation, and mechanical ventilation) |
Grade 1 | |
Fevera | Temp ≥38 ℃ |
With Hypotension | None |
And/orb Hypoxia | None |
Grade 2 | |
Fevera | Temp ≥38 ℃ |
With Hypotension | Not requiring a vasopressor |
And/orb Hypoxia | Requiring low-flow nasal cannulac or blow-by |
Grade 3 | |
Fevera | Temp ≥38 ℃ |
With Hypotension | Requiring a vasopressor with or without vasopressin |
And/orb Hypoxia | Requiring high-flow nasal cannula,c face mask, non-rebreather mask, or Venturi mask |
Grade 4 | |
Fevera | Temp ≥38 ℃ |
With Hypotension | Requiring multiple vasopressors (excluding vasopressin) |
And/orb Hypoxia | Requiring positive pressure (eg, CPAP, BiPAP, intubation, and mechanical ventilation) |
ASTCT, American Society of Transplantation and Cellular Therapy; BiPAP, bilevel positive airway pressure; CPAP, continuous positive airway pressure; CRS, cytokine release syndrome; CTCAE, Common Terminology Criteria for Adverse Events.
Organ toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not influence CRS grading.
ASTCT Consensus Grading Guidelines for ICANS in Adults28
Grade 1 | Grade 2 | Grade 3 | Grade 4 | |
---|---|---|---|---|
ICE score (see below)a | 7‐9 | 3-6 | 0-2 | 0 (Patient is unarousable and unable to perform ICE) |
Depressed level of consciousnessb | Awakens spontaneously | Awakens to voice | Awakens only to tactile stimulus | Patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse. Stupor or coma. |
Seizure | N/A | N/A | Any clinical seizure, focal or generalized, that resolves rapidly or nonconvulsive seizures on EEG that resolve with intervention | Life-threatening prolonged seizure (>5 min); or repetitive clinical or electrical seizures without return to baseline in between |
Motor findingsc | N/A | N/A | N/A | Deep focal motor weakness such as hemiparesis or paraparesis |
Elevated ICP/cerebral edema | N/A | N/A | Focal/local edema on neuroimagingd | Diffuse cerebral edema on neuroimaging; decerebrate or decorticate posturing; or cranial nerve VI palsy; or papilledema; or Cushing’s triad |
Grade 1 | |
ICE score (see below)a | 7‐9 |
Depressed level of consciousnessb | Awakens spontaneously |
Seizure | N/A |
Motor findingsc | N/A |
Elevated ICP/cerebral edema | N/A |
Grade 2 | |
ICE score (see below)a | 3-6 |
Depressed level of consciousnessb | Awakens to voice |
Seizure | N/A |
Motor findingsc | N/A |
Elevated ICP/cerebral edema | N/A |
Grade 3 | |
ICE score (see below)a | 0-2 |
Depressed level of consciousnessb | Awakens only to tactile stimulus |
Seizure | Any clinical seizure, focal or generalized, that resolves rapidly or nonconvulsive seizures on EEG that resolve with intervention |
Motor findingsc | N/A |
Elevated ICP/cerebral edema | Focal/local edema on neuroimagingd |
Grade 4 | |
ICE score (see below)a | 0 (Patient is unarousable and unable to perform ICE) |
Depressed level of consciousnessb | Patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse. Stupor or coma. |
Seizure | Life-threatening prolonged seizure (>5 min); or repetitive clinical or electrical seizures without return to baseline in between |
Motor findingsc | Deep focal motor weakness such as hemiparesis or paraparesis |
Elevated ICP/cerebral edema | Diffuse cerebral edema on neuroimaging; decerebrate or decorticate posturing; or cranial nerve VI palsy; or papilledema; or Cushing’s triad |
ASTCT, American Society of Transplantation and Cellular Therapy; CTCAE, Common Terminology Criteria for Adverse Events; EEG, electroencephalogram; ICANS, immune effector cell–associated neurotoxicity syndrome; ICE, immune effector cell–associated encephalopathy; ICP, intracranial pressure; N/A, not applicable.
ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings, raised ICP/cerebral edema) not attributable to any other cause; for example, a patient with an ICE score of 3 who has a generalized seizure is classified as Grade 3 ICANS.
Neurologic Toxicity Grading and Management Guidance35
NT Gradea | Corticosteroids and Antiseizure Medication |
---|---|
Grade 1 |
|
Grade 2 |
|
Grade 3 |
|
Grade 4 |
|