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Page 60 Bhasin et al. J Transl Genet Genom 2024;8:55-76 https://dx.doi.org/10.20517/jtgg.2023.46

Figure 1. Schematic demonstrating the mechanism of action of BiTE & CAR-T. T-cell redirecting therapies targeting tumor-associated
antigen of interest. mAB: Monoclonal antibody; scFv: single-chain variable fragment; TAA: tumor-associated antigen.

cytokine release syndrome (CRS), immune effector-cell-associated neurotoxicity syndrome (ICANS), and
on-target off-tumor (OTOT) toxicity.

CRS is a well-documented adverse event that has been observed with T-cell redirecting therapies and is
characterized by an uncontrolled systemic inflammatory response as a result of high levels of pro-
inflammatory cytokines released during T-cell activation, namely IL-6, IFN, and GM- CSF. CRS can present
with a wide range of clinical manifestations that range from low-grade fevers to systemic organ failure [41,42] .
Mild to moderate CRS is treated supportively, while severe cases are treated with infusion cessation and
tocilizumab, an anti-IL-6 monoclonal antibody. Furthermore, studies have shown that CRS can be
prevented with prophylactic dexamethasone administration and step-wise dose escalation [41-43] .

ICANS is characterized as a neurologic toxicity associated with an increased systemic inflammatory
response seen with T-cell activation. The exact pathophysiologic mechanism of ICANS remains unclear;
however, it is hypothesized that activated T-cells interact and cause disruption to the blood-brain barrier
and result in subsequent local CNS inflammation. Clinical manifestations are broad and can range from
headache and dizziness to altered mental status and encephalopathy. Management of ICANS includes
infusion cessation and steroid administration, but the efficacy of steroids remains uncertain [44-46] . Pentosan
polysulfate, an antiadhesive drug, may prevent ICANS and is currently under active investigation
(NCT00274742) [26,45] .

OTOT toxicities occur when TAA target recognition occurs in non-neoplastic tissues and can result in
cellular lysis and unintentional tissue cross-reactivity. Toxicities have been observed at higher rates in
CAR-T therapy, possibly due to the shorter half-life of BiTE therapy. OTOT toxicity can be mitigated by
careful selection of TAA targets that have high expression in malignant tissues and low physiologic