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Page 6 of 14 Haydu et al. J Cancer Metastasis Treat 2021;7:36 https://dx.doi.org/10.20517/2394-4722.2021.39

incidence and severity of CRS and ICANS vary based on CAR T-cell product but tend to follow a
predictable course and are relatively manageable and reversible. The choice of co-stimulatory domain is an
important predictor of toxicity, with CD28 co-stimulation leading to a more rapid and higher peak
expansion of CAR T-cells compared to the more gradual expansion and longer persistence of T-cells
engineered with 4-1BB co-stimulation . In practice, the kinetics of CD28 co-stimulation appear to result in
[16]
a quicker onset and increased incidence and higher severity of toxicity compared to a 4-1BB co-stimulated
product. High tumor burden has also been shown to be predictive of severe CRS and neurotoxicity .
[23]
[28]
Cytokine release syndrome
Cytokine release syndrome is characterized by the presence of fever and in more severe cases can progress
to hypotension, hypoxia, capillary leak, organ injury, and delirium. Manifestations of CRS can affect almost
any organ system. The incidence of CRS with the CD28 co-stimulated axi-cel in ZUMA-1 was 93% for any-
grade CRS and 13% for severe (grade 3-4) CRS and occurred at a median of 2 days following CAR T-cell
infusion [10,18] . In the ZUMA-5 trial in indolent B-cell NHL, grade 3 or higher CRS occurred in 7% of axi-cel-
[13]
treated patients . In JULIET, the incidence of CRS with the 4-1BB co-stimulated tisa-cel was 58% for any-
grade and 22% for grades 3-4, with a median onset at day 3 . The TRANSCEND trial with the 4-1BB co-
[11]
stimulated liso-cel reported an incidence of any-grade CRS in 42% of patients with a median time to onset
at day 5, with only 2% of patients developing severe CRS . In the relapsed/refractory MCL studies, 91% of
[9]
patients treated with the CD28 co-stimulated brexu-cel in ZUMA-2 experienced CRS with grade 3 or higher
in 15% of patients , while in the TRANSCEND MCL cohort (4-1BB co-stimulated liso-cel), the overall
[12]
CRS rate was 50%, with only one grade 4 event and no grade 3 or 5 events . Of note, CRS was graded using
[25]
the Lee criteria in ZUMA-1, ZUMA-2, ZUMA-5, and TRANSCEND and by the University of
[29]
Pennsylvania scale in JULIET, which classifies more patients as grade 3 or 4 compared to Lee criteria.
Consequently, the difference in grading systems complicates direct comparisons of grade 3-4 CRS rates, but
there clearly does appear to be a lower CRS incidence and severity in patients treated with 4-1BB co-
stimulated products.

CRS management includes supportive measures with intravenous fluids, antipyretics, and supplemental
oxygen as needed. Treatment with the IL-6 receptor antagonist tocilizumab can rapidly resolve fevers and
vasopressor requirements in the majority of patients with severe CRS and is now FDA-approved for the
treatment of grade 2-4 CRS. The rate of tocilizumab use on trial was 43% for patients treated with axi-cel in
ZUMA-1, 15% for patients treated with tisa-cel in JULIET, and 20% for patients treated with liso-cel in
TRANSCEND [9-11] . In ZUMA-2, 59% of MCL patients treated with brexu-cel received tocilizumab .
[12]
Corticosteroids can also ameliorate CRS and may be given concurrently with tocilizumab for grade 2-4
toxicity. Use of rescue medications for CRS has not been independently associated with impaired anti-
tumor responses .
[10]

Neurologic toxicity
Patients who develop ICANS with CAR T-cell therapy most commonly present with confusion but can also
develop aphasia, somnolence, obtundation, seizures, and rarely cerebral edema. ICANS usually occurs in
patients who have already had CRS and onsets as CRS is peaking or resolving; only rarely will ICANS occur
in the absence of antecedent CRS. Neurologic toxicity has predominantly been graded with the Common
Terminology Criteria for Adverse Events (CTCAE). In the 3 pivotal DLBCL CAR T trials, the incidence of
neurotoxicity was 64% for axi-cel (28% of patients with grade ≥ 3), 21% for tisa-cel (12% of patients with
grade ≥ 3), and 30% for liso-cel (10% of patients with grade ≥ 3) [9-11] . In ZUMA-5, grade 3 or higher
neurologic events occurred in 19% of FL or MZL patients treated with axi-cel . In the mantle cell CAR T
[13]
trials, the incidence of neurologic events was 63% for patients treated with brexu-cel (31% of patients with
grade ≥ 3) and 28% for patients treated with liso-cel (three grade 3 events and no grade 4 or 5 neurologic
[12]