Fig. 4.

An overview of combination therapy with CAR T cells. a Combination of CAR T cells with checkpoint inhibitors. b Combination of CAR T cells with immunosuppressive drugs. c Natural killer group 2D (NKG2D) ligand-based targeting by natural killer cells coupled with CAR T cells highlights a potential for combinatorial treatment. Extrinsic checkpoint blockade rests on programmed cell death 1 (PD-1) receptor/ligand hindering antibodies. Genetic engineering enables intrinsic PD-1 checkpoint blockage to express proteins or nucleic acid that disrupt PD-1/PD-L1 signaling. The PD-1 dominant negative receptor, which competes with native PD-1 receptor and inhibits inhibitory signaling through native wild-type receptors, lacks the intracellular signaling domain in its creation. PD-1/PD-L1 inhibiting single-chain variable fragments (ScFvs), which provide local antibody inhibition of PD-1 receptor/ligand interaction, can also be ensured by CAR T cells. Furthermore, gene-editing techniques can eliminate PD-1 expression by editing the programmed cell death protein 1 gene locus. CAR T cell therapy coupled with immunosuppressants attenuates non-specific toxicities by suppressing inflammation. The usefulness of combination therapy in the treatment of cancer is reinforced by the fact that NKG2D ligand-based targeting of natural killer cells in conjunction with CAR T cells enhances the anticancer effect of CAR T cells