CAR-T cell therapy toxicity

The most common toxicities associated with CAR T cell, therapies are cytokine release syndrome and neurotoxicity.

Additional toxicities, such as hypogammaglobulinemia, are a direct result of an on target/off-tumor activity of the CAR T cells, and others, such as infections may occur as an indirect consequence of an immunosuppressed state. 

The three main types of toxicities include: (a) cytokine release syndrome (CRS), which is caused by massive cytokine levels and T cell expansion; (b) hemophagocytic lymphohistiocytosis and/or macrophage activation syndrome (HLH/MAS), which is characterized as a hyperinflammatory state of CRS plus elevated serum ferritin and hemophagocytosis, renal failure, elevated liver enzymes, splenomegaly, pulmonary edema, and/or absence of NK cell activity; and (c) immune effector cell-associated neurotoxicity syndrome (ICANS), which is associated with increased cerebrospinal fluid cytokine levels and disruption of the blood-brain barrier.

CAR-T cells have caused significant morbidity and mortality via these three main toxicity syndromes.

A baseline cardiac assessment is recommended before initiation of CAR T cell infusion. 

Seizure prophylaxis is often used on the day of infusion, especially for CAR T cell therapy is known to cause more severe neurotoxicities.

All patients should receive baseline neurologic evaluation, including immune effector cell associated encephalopathy scores prior to CAR T cell therapy. 

Some institutions require baseline brain MRI and assessment of C reactive protein, and serum ferritin levels are recommended at baseline. 

Hospitalization or extremely close outpatient monitoring is recommended. 

Hospitalization is warranted for patients at the first sign of CRS or neurotoxicity, including fever, hypotension, or a change in mental status. 

Complete blood count, metabolic panel, coagulation profiles are monitored daily. 

CRP and serum ferritin are we checked at least three times a week for two weeks post infusion.

Frequent monitoring of vital signs is required during the first one to two weeks post infusion.

Neurotoxicity assessment is done at  twice daily.

Patient should refrain from driving or hazardous activities for at least eight weeks after infusion.

The timing, frequency, severity, and optimal management of CAR T cell related toxicity, varies between drugs.

CRS is defined as a super physiological response, following any immune therapy that results in the activation or engagement of endogenous, or infused T cells and/or other immune effector cells, such as lymphocytes on myeloid  cells.

CRS manifestations may include: fever, hypotension, tachycardia, hypoxemia, chills, may be associated with cardiac, hepatic, and/or renal dysfunction, atrial fibrillation, ventricular, tachycardia, cardiac arrest, cardiac failure, renal insufficiency, and capillary leak syndrome.

Cardiovascular complications of CRS can be severe and even fatal, requiring careful patient selection and close monitoring. 

The time to onset for CRS is 2 to 3 days with  duration of 7 to 8 days: CRS me occur within hours, of the CAR T-cell infusion and as  late as 10 to 15 days post infusion. 

Multiple cytokines have been implicated in CRS: IL-6, IL-1, IFN-gamma, and TNF-alpha. 

IL-6 is considered the primary mediator of CRS.

IL-6normally binds to membrane-bound IL-6receptor on certain immune effector cells and has anti-inflammatory properties. 

When IL-6 levels are increased in CRS, it may bind to a soluble form of IL-6 inducing a pro inflammatory response by activation of a trans signaling pathway. 

Neurotoxicity commonly occurs with CAR-T cell therapies.

The neurotoxicity that occurs with CAR T cell, therapies is termed immune effector cell associated neurotoxicity syndrome (ICANS).

 ICANS is defined by CNS activation engages, endogenous, or infused T cells, or other  immune effector cells.

ICANS can manifest as encephalopathy, delirium, aphasia, lethargy, headache, tremor, myoclonus, dizziness, motor dysfunction, and signs of psychosis, with characteristic features, including language disturbances.

The typical time to onset of neurotoxicity is 4 to 10 days after receiving CAR T cell therapy with a duration of 14 to 17 days.

CAR T cell related neurotoxicity is thought to result from endothelial cell activation, and leak into the CNS leading to elevated inflammatory cytokines in the CSF.

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