Table 2.

Therapies envisioned to circumvent resistance mechanisms due to cancer cells

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, 39–43] Tandem or bicistronic CARs [44–49]
	Target tumor cells independently of the CAR T target	“Armored” CAR T cells [50–54] 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 [66–68] Anti-PD1-secreting CAR T cells [69]
	PD-L1-resistant CAR T cells	PD1-KO [70–72] 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] Cyclooxygenase-2 (COX2) inhibitors [84, 85]
	Enhance sensitivity to CAR T cell killing	Smac mimetics (IAP inhibitors) [80] Bcl2 inhibitors [80, 86, 87]