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Table 2 Therapies envisioned to circumvent resistance mechanisms due to cancer cells

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]

Tandem or bicistronic CARs [44,45,46,47,48,49]

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-KO [70,71,72]

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]