Some CAR T therapies are approved and some are being investigated in clinical trials.

Defining CAR T Associated Toxicities


 

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.26,27

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.26-28

  • 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.28

  • 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

CRS and Neurotoxicity: Onset and Duration1,26,28,29

Table featuring common signs and symptoms of CRS and neurotoxicity following CAR T cell therapy infusion Table featuring common signs and symptoms of CRS and neurotoxicity following CAR T cell therapy infusion

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.25,33

  1. 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
  2. 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:

Warning Icon
  • Presence of comorbidities and compromised organ function27
  • High disease burden27
  • Presence of infection at the time of CAR T cell infusion, which would preclude or delay the use of CAR T cell therapy27
  • Presence of immunodeficiency or autoimmune disease27
  • High doses of infused CAR T cells in certain patients26
 

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 includes1,27,29:

Icon of a checklist
Careful monitoring for symptom onset—notably fever ≥38 °C/100.4 °F—as an early sign of CRS, as well as a sign of other AEs, such as infection1,28
IV Icon
Applying interleukin-6 (IL-6) blockade using tocilizumab to help manage CRS-related toxicities Grade ≥2, such as fevers and hemodynamic instability27,28
Icon of nurse’s hat
Managing mild symptoms with appropriate intervention and supportive care, including steroids1,28,33
Icon of hospital bed
Considering ICU-level care for severe symptoms1,28

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.28

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.28

ASTCT Consensus Grading Guidelines for CRS28

Grade 1Grade 2Grade 3Grade 4
FeveraTemp ≥38 ℃Temp ≥38 ℃Temp ≥38 ℃Temp ≥38 ℃
With HypotensionNoneNot requiring a vasopressorRequiring a vasopressor with or without vasopressinRequiring multiple vasopressors (excluding vasopressin)
And/orb HypoxiaNoneRequiring low-flow nasal cannulac or blow-byRequiring high-flow nasal cannula,c face mask, non-rebreather mask, or Venturi maskRequiring positive pressure (eg, CPAP, BiPAP, intubation, and mechanical ventilation)

Grade 1
FeveraTemp ≥38 ℃
With HypotensionNone
And/orb HypoxiaNone
Grade 2
FeveraTemp ≥38 ℃
With HypotensionNot requiring a vasopressor
And/orb HypoxiaRequiring low-flow nasal cannulac or blow-by
Grade 3
FeveraTemp ≥38 ℃
With HypotensionRequiring a vasopressor with or without vasopressin
And/orb HypoxiaRequiring high-flow nasal cannula,c face mask, non-rebreather mask, or Venturi mask
Grade 4
FeveraTemp ≥38 ℃
With HypotensionRequiring multiple vasopressors (excluding vasopressin)
And/orb HypoxiaRequiring 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.

aDefined as temperature ≥38 °C not attributable to any other cause. In patients who have CRS then receive antipyretic or anticytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia.
bCRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with temperature of 39.5 °C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified as Grade 3 CRS.
cLow-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. Low flow also includes blow-by oxygen delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 L/minute.

ASTCT Consensus Grading Guidelines for ICANS in Adults28

Grade 1Grade 2Grade 3Grade 4
ICE score (see below)a7‐93-60-20 (Patient is unarousable and unable to perform ICE) 
Depressed level of consciousnessbAwakens spontaneouslyAwakens to voiceAwakens only to tactile stimulusPatient is unarousable or requires vigorous or repetitive tactile stimuli to arouse. Stupor or coma.
SeizureN/AN/AAny clinical seizure, focal or generalized, that resolves rapidly or nonconvulsive seizures on EEG that resolve with interventionLife-threatening prolonged seizure (>5 min); or repetitive clinical or electrical seizures without return to baseline in between
Motor findingscN/AN/AN/ADeep focal motor weakness such as hemiparesis or paraparesis
Elevated ICP/cerebral edemaN/AN/AFocal/local edema on neuroimagingdDiffuse 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)a7‐9
Depressed level of consciousnessbAwakens spontaneously
SeizureN/A
Motor findingscN/A
Elevated ICP/cerebral edemaN/A
Grade 2
ICE score (see below)a3-6
Depressed level of consciousnessbAwakens to voice
SeizureN/A
Motor findingscN/A
Elevated ICP/cerebral edemaN/A
Grade 3
ICE score (see below)a0-2
Depressed level of consciousnessbAwakens only to tactile stimulus
SeizureAny clinical seizure, focal or generalized, that resolves rapidly or nonconvulsive seizures on EEG that resolve with intervention
Motor findingscN/A
Elevated ICP/cerebral edemaFocal/local edema on neuroimagingd
Grade 4
ICE score (see below)a0 (Patient is unarousable and unable to perform ICE) 
Depressed level of consciousnessbPatient is unarousable or requires vigorous or repetitive tactile stimuli to arouse. Stupor or coma.
SeizureLife-threatening prolonged seizure (>5 min); or repetitive clinical or electrical seizures without return to baseline in between
Motor findingscDeep focal motor weakness such as hemiparesis or paraparesis
Elevated ICP/cerebral edemaDiffuse 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.

aA 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.
bDepressed level of consciousness should be attributable to no other cause (eg, no sedating medication).
cTremors and myoclonus associated with immune effector cell therapies may be graded according to CTCAE v5.0, but they do not influence ICANS grading.
dIntracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded from ICANS grading. It may be graded according to CTCAE v5.0.

ICE Score

Orientation: orientation to year, month, city, hospital: 4 POINTS
Naming: ability to name 3 objects (eg, point to clock, pen, button): 3 POINTS
Following commands: ability to follow simple commands (eg, “Show me 2 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
 
Scoring
0, no impairment
7-9, Grade 1 ICANS
3-6, Grade 2 ICANS
0-2, Grade 3 ICANS
0, due to patient unarousable and unable to perform ICE assessment, Grade 4 ICANS

Neurologic Toxicity Grading and Management Guidance35

NT GradeaCorticosteroids and Antiseizure Medication 
Grade 1
  • Start nonsedating, antiseizure medicines (eg, levetiracetam) for seizure prophylaxis.
  • If 72 hours or more after infusion, observe.
  • If less than 72 hours after infusion, consider dexamethasone 10 mg IV every 12 to 24 hours for 2 to 3 days.
Grade 2
  • Start nonsedating, antiseizure medicines (eg, levetiracetam) for seizure prophylaxis.
  • Dexamethasone 10 mg IV every 12 hours for 2 to 3 days, or longer for persistent symptoms. Consider taper for a total steroid exposure of greater than 3 days.
  • If no improvement after 24 hours or worsening of neurologic toxicity, increase the dose and/or frequency of dexamethasone up to a maximum of 20 mg IV every 6 hours.
  • If no improvement after another 24 hours, rapidly progressing symptoms, or life-threatening complications arise, give methylprednisolone (2 mg/kg loading dose, followed by 2 mg/kg divided 4 times a day; taper within 7 days).
Grade 3
  • Start nonsedating, antiseizure medicines (eg, levetiracetam) for seizure prophylaxis.
  • Dexamethasone 10 to 20 mg IV every 8 to 12 hours. Steroids are not recommended for isolated Grade 3 headaches.
  • If no improvement after 24 hours or worsening of neurologic toxicity, escalate to methylprednisolone (dose and frequency as per Grade 2).
  • If cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1-2 g, repeat every 24 hours if needed; taper as clinically indicated) and cyclophosphamide 1.5 mg/m2.
Grade 4
  • Start nonsedating, antiseizure medicines (eg, levetiracetam) for seizure prophylaxis.
  • Dexamethasone 20 mg IV every 6 hours.
  • If no improvement after 24 hours or worsening of neurologic toxicity, escalate to methylprednisolone (dose and frequency as per Grade 2).
  • If cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1-2 g, repeat every 24 hours if needed; taper as clinically indicated), and cyclophosphamide 1.5 mg/m2.

aNCI CTCAE criteria for grading neurologic toxicities.
Patient considerations for CAR T cell therapy >
For downloadable content on acute management, visit CAR T Academy

References: 1. Maus MV, Levine BL. Oncologist. 2016;21:608-617. 2. Dotti G, Gottschalk S, Savoldo B, et al. Immunol Rev. 2014;257:107-126. 3. Sadelain M, Brentjens R, Rivière I. Cancer Discov. 2013;3:388-398. 4. Ajina A, Maher J. Mol Cancer Ther. 2018;17:1795-1815. 5. Maus MV, June CH. Clin Cancer Res. 2016;22:1875-1884. 6. Kawalekar OU, O'Connor RS, Fraietta JA, et al. Immunity. 2016;44:380-390. 7. Dai H, Wang Y, Lu X, Han W. J Natl Cancer Inst. 2016;108:1-14. 8. Porter DL, Hwang WT, Frey NV, et al. Sci Transl Med. 2015;7:303ra139. doi:10.1126/scitranslmed.aac5415. 9. Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular Immunology. 9th ed. Philadelphia, PA: Saunders Elsevier; 2018. 10. Hartmann J, Schüßler-Lenz M, Bondanza A, Buchholz CJ. EMBO Mol Med. 2017;9:1183-1197. 11. Tai YT, Anderson KC. Immunotherapy. 2015;7:1187-1199. 12. Park JH, Brentjens RJ. Discov Med. 2010;9:277-288. 13. Tai YT, Mayes PA, Acharya C, et al. Blood. 2014;123:3128-3138. 14. D’Aloia MM, Zizzari IG, Sacchetti B, et al. Cell Death Dis. 2018;9:282. doi:10.1038/s41419-018-0278-6. 15. Khalil DN, Smith EL, Brentjens RJ, Wolchok JD. Nat Rev Clin Oncol. 2016;13:273-290. 16. Abate-Daga D, Davila ML. Mol Ther Oncolytics. 2016;3:16014. 17. Watanabe N, Bajgain P, Sukumaran S, et al. Oncoimmunology. 2016;5:e1253656. 18. Zhao Z, Condomines M, van der Stegen SJ, et al. Cancer Cell. 2015;28:415-428. 19. Mahnke YD, Brodie TM, Sallusto F, et al. Eur J Immunol. 2013;43:2797-2809. 20. Brudno JN, Kochenderfer JN. Blood Rev. 2019;34:45-55. 21. Turtle CJ, Hanafi LA, Berger C, et al. J Clin Invest. 2016;126:2123-2138. 22. Restifo NP, Dudley ME, Rosenberg SA. Nat Rev Immunol. 2012;12(4):269-281. 23. Fagnoni FF, Lozza L, Zibera C, et al. Immunology. 2002;106:27-37. 24. Stock S, Schmitt M, Sellner L. Int J Mol Sci. 2019;20:6223. doi:10.3390/ijms20246223. 25. Batlevi CL, Matsuki E, Brentjens RJ, Younes A. Nat Rev Clin Oncol. 2016;13:25-40. 26. Hay KA. Br J Haematol. 2018;183(3):364-374. 27. Brudno JN, Kochenderfer JN. Blood. 2016;127(26):3321-3330. 28. Lee DW, Santomasso BD, Locke FL, et al. Biol Blood Marrow Transplant. 2019;25(4):625-638. 29. Neelapu SS, Tummala S, Kebriaei P, et al. Nat Rev Clin Oncol. 2018;15(1):47-62. 30. Rubin DB, Danish HH, Ali AB, et al. Brain. 2019;142(5):1334-1348. 31. Teachey DT, Bishop MR, Maloney DG, Grupp SA. Nat Rev Clin Oncol. 2018;15(4):218. doi:10.1038/nrclinonc.2018.19. 32. Wang Z, Han W. Biomark Res. 2018;6:4. doi:10.1186/s40364-018-0116-0. 33. Chavez JC, Bachmeier C, Kharfan-Dabaja MA. Ther Adv Hematol. 2019;10:1-20. 34. Brudno JN, Maric I, Hartman SD, et al. J Clin Oncol. 2018;36(22):2267-2280. 35. US Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0. November 27, 2017.