Chimeric antigen receptors: On the road to realising their full potential

Table 1 Summary of toxicities that may be attributed to immunotherapy using chimeric antigen receptor engineered T-cells

On target on tumour toxicity
Cytokine release syndrome[32]	Exaggerated activation of multiple leukocyte subtypes
	Marked elevation in circulating levels of multiple cytokines
	Pyrexia and acute phase response
	Vascular leakage
	Failure of one or more major organs
	May be related to tumour burden
	Occurs days to (exceptionally) weeks after T-cell infusion
Macrophage activation	Haemophagocytosis
syndrome[25]	Organomegaly
	Elevation of ferritin, aminotransferases, lactate dehydrogenase and triglycerides
	Hypofibrinogenemia
Tumour lysis syndrome	Rapid tumour cell destruction leading to profound metabolic disturbances, including hyperphosphatemia, hyperuricaemia, hyperkalaemia, hypocalcaemia and/or renal failure
On target off tumour toxicity
CAR T-cell mediated immune attack of healthy tissue that express cognate target	Exemplified by
	B-cell aplasia induced by CD19-targeted CAR T-cells[23-28]
	hepatotoxicity induced by carbonic anhydrase IX-targeted CAR T-cells[37]
	pulmonary toxicity induced by HER2-targeted CAR T-cells[38]
Antibody mediated toxicity	Exemplified by
	anaphylaxis induced by mesothelin-targeted CAR T-cells[42]
Off target off tumour toxicity
Insertional mutagenesis	Not seen with gene-modified T-cells as yet, unlike haemopoietic stem cells
Replication competent virus	Not seen with modern vector systems

CAR: Chimeric antigen receptor.