Table 1.

Comparison of the CAR T cell generations.

Generations	Main cytoplasmic domains	Co-stimulatory domain	Drawback
1st generation	A single CD3 ζ-chain	None	Failure to produce adequate IL-2, low cell proliferation, higher toxicities, and brief in vivo persistence
2nd generation	CD3 ζ-chain	CD28 for dual signaling	CAR T cell exhaustion
3rd generation	CD3 ζ-chain	CD28 and 4-1BB	Adapted persistence and proliferation yet no enhanced efficacy as compared to earlier generations
4th generation	CD3 ζ-chain	CD28 and IL-12 inducer domain	Off-target/off-tumor toxicity
5th generation	CD3 ζ-chain	Cytoplasmic IL-2 receptor β-chain domain activating antigen-mediated JAK/STAT pathway	Not yet approved Preoccupied with concerns on immunogenicity and high costs