Fig. 4

The usage and progress of CAR-T cell therapy. In CAR T-cell therapy, the patient's T cells are collected and sent to a lab. In the lab, they are genetically modified to recognize target lymphoma cells. These genetically modified T cells are named CAR-T cells. After that, the CAR-T cells are expanded in the lab until there are enough to treat the lymphoma cells. Then, CAR-T cells are returned to the patient, like a blood transfusion. When they recognize the lymphoma cells in the body, the CAR-T cells are activated and kill the lymphoma cells (a). There are currently five generations of CAR-T cell products. The first-generation, composed of scFv and CD3ξ, is a single chain approach based on the scFv, which joins the antibody's heavy and light variable gene segments with a flexible linker. Second-generation CARs contain the scFv and CD3ξ components present in the first-generation together with a costimulatory domain, which markedly increases T-cell proliferation and interleukin -2 secretion. Axi-cel contains a CD28 costimulatory domain, while Tisa-cel and Liso-cel contain the 4-1BB costimulatory domain. The third-generation CARs contain both CD28 and 4-1BB and have superior expansion and longer persistence than the second-generation CARs. Fourth-generation CARs incorporate a transgenic cytokine sequence and counteract the immunosuppressive microenvironment in tumors. The fifth-generation CARs encode a truncated cytoplasmic domain of IL-2Rb and a STAT3- binding YXXQ motif together with scFv targeting CD19, CD3z, and CD28 domains, which show better proliferation and cytokine polyfunctionality compared to second-generation CARs (b). NK cells do not require HLA matching like T cells. It makes “off-the-shelf” NK cell therapy a viable option. CAR NK cells will release perforin and granzymes to kill tumor cells (c). Most CAR-T therapies consist of autologous T cells, whereas CAR-NK cell therapies can be generated from allogeneic donors