Exhaustion of CAR T cells: potential causes and solutions

Table 1 Comparison of chimeric antigen receptors (CARs) with and without tonic signaling

Antigen	CD19	c-Met	GD2
CAR construct	Second-generation with CD28	Second-generation with CD28	Second-generation with CD28
Ex vivo proliferation	~ 2 weeks without stimulation	Continuous without stimulation	Poor
Ex vivo killing activity	Good	Good	Good
IL-2 expression	Moderate	Increased	Defective
Ex vivo exhaustion	No	Upregulation of T-bet and EOMES	Upregulation of inhibitory molecules such as PD-1, LAG3 and TIM-3
In vivo persistence	Good	Poor	Poor
Reference	[33]	[27]	[9]

The characteristics of three types of CARs are compared. c-Met and GD2 CARs show tonic signaling, while CD19 CAR does not. Note that although c-Met and GD2 CARs show opposite phenotypes in some properties, they both indicate exhaustion to various extents

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