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. 2021 Nov 22;14:199. doi: 10.1186/s13045-021-01209-9

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, 3943]

Tandem or bicistronic CARs [4449]

Target tumor cells independently of the CAR T target

“Armored” CAR T cells [5054]

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 [6668]

Anti-PD1-secreting CAR T cells [69]

PD-L1-resistant CAR T cells

PD1-KO [7072]

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]