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.

Table 2 Clinical trials of chimeric antigen receptor T-cell immunotherapy of haematological malignancy

Target	No. of trials	Diseases
CD19	40	Acute and chronic B-cell malignancies
		Hodgkin’s lymphoma
CD30	4	Hodgkin’s lymphoma; CD30+ non-Hodgkin’s lymphoma
CD20	2	B-cell malignancy
CD22	1	B-cell malignancy
Kappa light chain	1	B-cell malignancy
		Multiple myeloma
CD33	1	Acute myeloid leukaemia
CD138	1	Multiple myeloma
CD123	1	Acute myeloid leukaemia
Lewis Y antigen		Acute myeloid leukaemia Myelodysplastic syndrome;
		Multiple myeloma
NKG2D stress ligands	1	Acute myeloid leukaemia; Myelodysplastic syndrome;
		Multiple myeloma
Combinatorial	1	CD16-containing "universal CAR" targeted with rituximab for B-cell malignancy

CAR: Chimeric antigen receptor.

Table 3 Clinical trials of chimeric antigen receptor T-cell immunotherapy of solid tumours and other diseases

Target	No. of trials	Diseases
HER2	7	Glioblastoma
		HER2 expressing solid tumours1
GD2	7	Neuroblastoma[34]
		GD2-expressing malignancy
		Osteosarcoma
		Melanoma
Mesothelin	4	Pancreatic cancer[40]
		Ovarian cancer
		Mesothelioma2
CEA	4	Breast cancer
		CEA expressing malignancy1
Folate receptor-α	1	Epithelial ovarian cancer[29]
EGFr	2	EGFr+ malignancy
		Glioblastoma
EGFr variant III	2	Glioblastoma
Carbonic anhydrase IX	1	Renal cell carcinoma[37]
Prostate-specific membrane antigen	2	Castrate-resistant prostate cancer
Interleukin-13 receptor α2	1	Glioma[43]
CD171 (L1 cell adhesion molecule)	1	Neuroblastoma
Extended ErbB family	1	Head and neck cancer3[20]
Fibroblast-activation protein	1	Mesothelioma
Glypican-3	1	Hepatocellular carcinoma
Pathogenic T-cell receptors	1	Type 1 diabetes4

(https://clinicaltrials.gov/accessed August 26^th, 2015 search terms: T cell gene cancer; chimeric and cancer; T-cell cancer and gene).

¹One Trial terminated due to toxicity;

²Trial includes the co-administration of CD19-targeted CAR T-cells to minimize anti-CAR antibody production; ³Intra-tumoural route in use to minimize toxicity;

⁴CAR targeted using a peptide + HLA-CD3ξ fusion; CAR: Chimeric antigen receptor; CEA: Carcinoembryonic antigen; EGFr: Epidermal growth factor receptor.