From Immune Dysregulations to Therapeutic Perspectives in Myelodysplastic Syndromes: A Review
Abstract
:1. Introduction
2. Inflamm-Aging as a Risk for Clonal Hematopoiesis
3. Smoldering Inflammation Acts Early in MDS Pathophysiology
3.1. Proinflammatory Cytokines
3.2. NLRP3 Inflammasome
3.3. Toll-like-Receptors (TLR)
3.4. Immune Cells
4. Positive and Negative Immune Regulators
4.1. Co-Stimulatory Molecules
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- OX40, Inducible T-cell COStimulator (ICOS) and 4-1BB+: Tumor protein 3 (TP53) MDS patients display reduced numbers of OX40+ cytotoxic T-cells and helper T-cells, as well as reduced ICOS+ and 4-1BB+ NK-cells [74].
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4.2. Coinhibitory Molecules
5. Opposite Adaptive Dysfunctions in LR and HR-MDS
6. Immune Phenotypes Can Be Associated with Somatic Mutations
7. Immune Strategies in MDS: Past, Present and Future
7.1. “Old” Treatments
7.2. Targeting TGF-β Superfamily in LR-MDS with Anemia
7.3. Targeting the Inflammasomes
7.4. Checkpoint Inhibitors
7.5. Targeting NK-Cells
7.6. Vaccination Strategies
7.7. Adoptive T-Cell Transfer Therapy
Molecule | Patients | NCT/Phase/Status | Ref. | |
---|---|---|---|---|
Cytokines | ||||
TGF-β | Luspatercept | LR-MDS with anemia | NCT02604433/Phase III/Authorization | [126] |
TNF-α | Etanercept | HR-MDS (+Aza) | NCT00118287/I-II/Completed | [122] |
IL-1 | Canakinumab | LR-MDS (+Aza) LR-MDS (+luspa, +TIM3inh) | NCT04239157/II/Recruiting NCT04810611/Ib/Recruiting | |
Inflammasome | ||||
IRAK-4 | CA-4948 | HR-MDS (+aza and/or Ven) | NCT04278768/I-II/Recruiting | [128] |
NLRP3 | ibrutinib | HR-MDS (+Aza) HR-MDS (+Len) | NCT02553941/I/Recruiting NCT03359460/I/Recruiting | [129] |
TLR | ||||
TLR-4 | CX-01 | HR-MDS (+Aza) | NCT02995655/I/Completed | [131] |
TLR-2 | OPN-305 | LR-MDS | NCT02363491/I-II/Completed | [132] |
NF-kB | Bortezomib | HR-MDS (+Len) | NCT00580242/I/completed | [130] |
MDSC | ||||
CD33 inh | BI 836858 | LR-MDS | NCT02240706/II/Terminated | |
Immune check-points | ||||
CTLA-4 | ipilimumab | HR-MDS HR-MDS (and/or nivolumab +/−Aza) HR-MDS (+Dec) | NCT01757639/I/Completed NCT02530463/II/recruiting NCT02890329/I/Recruiting | [134,135] |
PD-1 | Nivolumab Prembrolizumab PDR001 | HR-MDS (and/or ipi +/−Aza) HR-MDS (+chemo) HR-MDS (+Aza) HR-MDS(+Dec) HR-MDS (+Aza+/Tim3 inh) | NCT02530463/II/recruiting NCT02464657/II/completed NCT03094637/II/recruiting NCT03969446/I/recruiting NCT03066648/I/active | [135,137,139] |
PD-L1 | Durvalumab Atezolizumab | HR-MDS (+Aza) HR-MDS (+Guadecitabine) HR-MDS (+/−Aza) | NCT02775903/II/active NCT02935361/I-II/active NCT02508870/I/completed | [141,143,179] |
TIM3 | Sabatolimab (MBG453) | HR-MDS (+Aza+/−PD-1 inh) HR-MDS (+Aza) HR-MDS (+Aza+Ven) | NCT03066648/I/active NCT04266301/III/Recruiting NCT04812548/II/recruiting | [145,146] |
CD70 | Cusatuzumab (ARGX-110) | HR-MDS (+Aza) HR-MDS (+Aza) | NCT04241549/I/Active NCT03030612/I-II/Active | [146] |
CD47 | AK117 Hu5F9-G4 CC-90002 ALX148 Magrolimab | HR-MDS (+Aza) HR-MDS HR-MDS HR-MDS (+Aza) HR-MDS (+/−Aza) HR-MDS (+Aza) | NCT04900350/I-II/Recruiting NCT02678338/I/completed NCT02641002/I/Terminated NCT04417517/I-II/recruiting NCT03248479/I/completed NCT04313881/III/recruiting | [152,153] |
NK-cells | ||||
CD16/IL-15/CD33 | GTB-3550 TriKE™ | HR-MDS | NCT03214666/I-II/recruiting | [156] |
KIR inh | Lirilumab | HR-MDS (+/−Aza) | NCT02599649/II/terminated | [157] |
CAR-T-cells | ||||
Cyad-O1/02 | Cyad-O1/02 | HR-MDS | NCT03466320/I-II/completed, NCT04167696/I/recruiting | [178] |
NKX101 | NKX101 | HR-MDS | NCT04623944/I/Recruiting | [179] |
Prgn-3006 | Prgn-3006 | HR-MDS | NCT03927261/I/recruiting | [180] |
Vaccine | ||||
DSP-7888 | LR and HR-MDS | NCT02436252/I-II/completed | [158] | |
K562/GM-CSF/CD40L | HR-MD | NCT00840931/I/Completed | [175] | |
NPMW | HR-MDS | NCT02750995/I/completed | [173] |
8. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Comont, T.; Treiner, E.; Vergez, F. From Immune Dysregulations to Therapeutic Perspectives in Myelodysplastic Syndromes: A Review. Diagnostics 2021, 11, 1982. https://doi.org/10.3390/diagnostics11111982
Comont T, Treiner E, Vergez F. From Immune Dysregulations to Therapeutic Perspectives in Myelodysplastic Syndromes: A Review. Diagnostics. 2021; 11(11):1982. https://doi.org/10.3390/diagnostics11111982
Chicago/Turabian StyleComont, Thibault, Emmanuel Treiner, and François Vergez. 2021. "From Immune Dysregulations to Therapeutic Perspectives in Myelodysplastic Syndromes: A Review" Diagnostics 11, no. 11: 1982. https://doi.org/10.3390/diagnostics11111982