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1972
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This article is review of Chimeric antigen receptor (CAR) T cells which are genetically engineered T cells. These cells constitute a powerful new class of therapeutic agents that offer hope for curative responses in patients with cancer especially in the treatment of leukemia and lymphoma.
The two most common toxicities attributable to CAR T-cell therapy are CRS (cytokine release syndrome) and ICANS (immune effector cell‐associated neurotoxicity syndrome). The frequency of these toxicities strongly depend on the patient population and the type of CAR T-cell product used. However, it is safe to say that CRS is more common than ICANS.
Time to detection:
CRS and ICANS are observed acutely after CAR T-cell infusion (<2 weeks). ICANS typically occurs after CRS has subsided.
Alerting signals, symptoms, evidence of occurrence:
Many of the toxic effects that are reported with CAR T cells are on-target effects. Their spectrum depends on the specificity of antibody single-chain variable fragments and T-cell activation. These toxic effects are thus reversible when the target cell is eliminated or the engraftment of the CAR T cells is terminated. Some of the side effects reported are B-cell aplasia and hypogammaglobulinemia, cytokine release syndrome (which can be lethal).
The CRS manifests with a noninfectious flulike syndrome. The onset of the cytokine release syndrome correlates with the pharmacokinetic characteristics of the CAR T cells, with a temporal association between the syndrome and peak levels of CAR T-cells. On the other hand, ICANS typically presents as a toxic encephalopathy with word‐finding difficulty, aphasia, and confusion but can progress in more severe cases to depressed level of consciousness, coma, seizures, motor weakness, and cerebral edema.
Demonstration of imputability or root cause:
The onset of CRS correlates with the pharmacokinetic characteristics of the CAR T cells, with a temporal association between the syndrome and peak levels of CAR T-cells. Also, CRS is an on-target toxic effect and is not common in patients who do not have a clinical response after CAR therapy. The pathophysiology of ICANS is less well understood than CRS. Like CRS, cytokines, chemokines, and degree of CAR T‐cell expansion have been associated with severity of neurotoxicity.
Imputability grade:
3 Definite/Certain/Proven
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Suggest references:
1) Chimeric Antigen Receptor Therapy. N Engl J Med. 2018 Jul 5;379(1):64-73
2) Comment in A Look Forward - The Frontiers in Medicine Series. [N Engl J Med. 2018 Jul 5;379(1):85-86]
Expert comments for publication:
Review article on Chimeric antigen receptor (CAR) T cells