Table 1.

Different generations of CAR‐T cells

Generation	First generation	Second generation	Third generation	Fourth generation
Composition of CAR	scFv, hinge, Fc receptor γ or CD3 ζ signaling chain	scFv, hinge, transmembrane region, one costimulatory domain, CD3 ζ	scFv, hinge, transmembrane region, two costimulatory domains, CD3 ζ	scFv, hinge, transmembrane region, one or two costimulatory domains, CD3 ζ, transgenic payload (cytokines, antibodies, enzymes, etc)
Preclinical studies	Effective in vitro and in mouse models	Superior antitumor effects, improved persistence, and higher level of cytokine production than first‐generation CAR	Compared to second‐generation CAR‐T, showed enhanced antitumor potency in some studies	Improved the effector function of CAR‐T cells in suppressive tumor microenvironment of solid tumor; provided a safety switch
Summary of clinical results	Limited antitumor efficacy due to short persistence in vivo	Most often used in clinic, significant antitumor response in various hematological malignancies	Used in a few clinical studies and most of them are still ongoing. Limited data suggested good antitumor efficacies and modest toxicity in B cell malignancies	Clinical studies for hematological malignancies and solid tumors are still in the early stage
Reference	1, 2, 3, 4, 5, 6, 7, 8, 9, 10	11, 12, 13, 14	15, 16	17

Abbreviations: CAR, chimeric antigen receptor; scFv, single‐chain variable fragment.