Chimeric antigen receptor T cell therapy: Revolutionizing cancer treatment

Table 2 Summary of chimeric antigen receptor generations

CAR generation	Intracellular domain structure	Key features and limitations	Pivotal trials1	Approved/trial phase
1st	ISD (e.g., CD3ζ); No CSD	Weak activation, limited proliferation and persistence; low clinical efficacy	None	None
2nd	ISD + 1 CSD (e.g., CD28 or 4-1BB)	Enhanced activation, cytokine release, persistence, and clinical efficacy. Limited long-term persistence	ELIANA: NCT01029366, NCT02435849[31]; (Kymirah), Zuma-1: NCT02348216	All 7 FDA-approved CAR-T therapies
3rd	ISD + 2 CSD (e.g., CD28 and 4-1BB)	Mixed results; no clear benefit over 2nd-gen; increased risk of severe CRS	HD-CAR-1 trial: (NCT03676504), ENABLE-1: (NCT04049513)	Phase I/II, Phase I
4th	(2nd generation CAR: ISD + 1 CSD) + secondary transgene (e.g., NFAT) for cytokine secretion	Inducible cytokine expression; potential to overcome antigen loss; risk of on-target/off-tumor effects	NCT03778346; NCT03542799	Phase I, Phase I
5th	2nd Generation CAR + IL-2 membrane receptor ISD (IL2Rβ here)	Integrates ISD, CSD, and cytokine signaling; monovalent design limits antigen coverage	NCT05665062; NCT05666635	Early Phase I, early Phase I,

¹Trials are listed with ClinicalTrials.gov identifier.

ISD: Intracellular signaling domain; CSD: Costimulatory domain; CRS: Cytokine release syndrome; CAR: Chimeric antigen receptor; FDA: United States Food and Drug Administration; NFAT: Nuclear factor of activated T cells.