CAR technology evolution through the generation of more potent CARs. First-generation CARs classically contain only one signaling domain, typically the cytoplasmic signaling domain of the CD3 TCRζ chain. Second-generation CARs containing 2 signaling domains typically include the addition of the cytoplasmic signaling domains of the costimulatory receptors CD28, 4-1BB, or OX-40, among others. Third-generation CARs attempt to harness the signaling potential of 2 costimulatory domains: classically, the CD28 domain followed by either the 4-1BB or OX-40 signaling domains. CAR-modified T-cell potency may be further enhanced through the introduction of additional genes, including those encoding proproliferative cytokines (ie, IL-12) or costimulatory ligands (ie, 4-1BBL), thus producing “armored” fourth-generation CAR-modified T cells.