From: Born to survive: how cancer cells resist CAR T cell therapy
Mechanism | Treatment | |
---|---|---|
Loss of target-Ag | CAR-T construct | Higher affinity scFvs [35, 36] Hinge region [36] |
Target multiple antigens | CAR T cells with different specificities [37, 39,40,41,42,43] | |
Target tumor cells independently of the CAR T target | “Armored” CAR T cells [50,51,52,53,54] TRAIL-mediated death (low-dose radiation) [55] | |
Reducing antigen loss on target cell surface | γ-secretase inhibitors [57] | |
Deplete transduced tumor cells in case of epitope masking | Anti-CAR19 idiotype CAR T cells [58] | |
Expression of inhibitory ligands (PD-L1) | Combination with CPI | CAR T cells + anti-PD1 Ab [66,67,68] Anti-PD1-secreting CAR T cells [69] |
PD-L1-resistant CAR T cells | PD1 dominant-negative receptor [73] PD1 switch receptor [74] | |
Lack of costimulatory ligand (CD58) | Provide CD2 costimulation independently of CD58 | CAR with a CD2 signaling domain [77] |
Resistance to immune killing | Enhance expression of death receptors | DNA damaging agents [81] Histone deacetylase (HDAC) inhibitors [82, 85] Proteasome inhibitors [83] |
Enhance sensitivity to CAR T cell killing | Smac mimetics (IAP inhibitors) [80] |