Table 6.
Mechanisms of resistance of leukemic stem cells (LSC) against immunotherapies.
| Mechanism | Possible Strategy to Overcome Resistance |
|---|---|
| Intrinsic resistance | Antibody-based targeting of LSC |
| LSC quiescence | Antibody-based targeting of LSC Priming LSC into the cell cycle |
| Expression of MDR | MDR-targeting drugs or CAR cells |
| Loss of cell surface targets | Mixtures of antibodies or CAR cells directed against two or more surface targets, drug combinations, or combination of drug therapy with HSCT |
| Immune checkpoint-induced LSC resistance | Checkpoint-targeting antibodies Checkpoint-targeting CAR cells BET/MYC-targeting drugs * JAK/STAT-targeting drugs |
| BM niche-related resistance | Niche cell-targeting drugs |
| Osteoblastic niche | BET/MYC-targeting drugs * |
| Vascular niche | Specific anti-angiogenic drugs |
| LSC retention in niche | Mobilizing drugs (plerixafor) |
| LSC hypermobilization | Mobilization blocker (e.g., gliptins) |
| General immunosuppression | Repeated T/NK cell infusion |
| Blocked immune cells | Bispecific antibodies against LSC and immune effector cells |
| Loss of CAR-T cells or CAR-NK cells |
Repeated infusions of CAR cells |
| Development of blocking antibodies against CARs | Use of single domain scFvs Humanize the scFvs |
* BET/MYC-targeting drugs can suppress cytokine-induced and oncogene-induced expression of PD-L1 on LSC in AML and CML as well as osteoblast-induced resistance. Abbreviations: LSC, leukemic stem cells; MDR, multi-drug resistance gene product; HSCT, hematopoietic stem cell transplantation; CAR, chimeric antigen receptor; NK cells; natural killer cells; scFvs, single chain variable fragments.