Table 1.
Inhibitory pathways in AML.
| Inhibitory pathway/check point | Physiological role | Role in AML | Clinical trials in AML |
|---|---|---|---|
| PD-1/PD-L1 axes |
PD-1—receptor of negative co-stimulation. Ligands: PD-L1 and PD-L2. PD-1/PD-L1 axes—control of normal immune responses, involved in periphery tolerance, autoimmunity regulation, allergy, infections, and antitumor immunity (87). |
PD-1/PD-L signaling—dampening of anti-leukemic immunity in AML. PD-L1 and PD-L2 expression on human AML cells at diagnosis and relapse (88). Blocking of PD-1/PD-L1 axis—increase of anti-leukemia immune response and prevention of AML progression in murine model (83, 84, 89). |
1. Anti-PD-1 Nivolumab: NCT02275533, NCT02397720, NCT02532231, NCT03092674, NCT02464657, NCT02275533, NCT03066648 Pembrolizumab: NCT02708641, NCT02845297, NCT02996474, NCT02771197, NCT02768792 Avelumab: NCT02953561 2. Anti-PD-L1 Durvalumab: NCT02775903 Atezolizumab: NCT02892318, NCT03154827 |
| CTLA-4 |
CTLA-4—receptor of negative co-stimulation. Ligands: CD80 and CD86. CTLA-4/CD80/CD86 pathway—regulation of T cell response (83). |
CTLA-4/CD80/CD86—hampering T cell immunity against hematological malignancies (83) and modulating immune responses in AML (90). Blocking of CTLA-4 pathway—increase of anti-leukemia T-cell immune response translated in prolonged tumor regression (91, 92). |
1. Anti-CTLA-4 Ipilimumab: NCT00039091, NCT02890329, NCT02397720 |
| CD200R/CD200 |
CD200R—inhibitory receptor. Ligand: CD200. CD200-CD200R signaling—down-regulation of immune responses preventing inflammation and immune pathology (83). |
CD200R/CD200—immunosuppressive signal transmission, macrophages inhibition, Tregs induction and tumor-specific T cells inhibition (93).Expression of CD200 on human AML cells (94)—worse overall survival of some AML subsets (83). Blocking of CD200—enhanced cytotoxicity of NK cells, restored proliferative capacity of T cells, dampens tumor-reactive immune responses (95), but also favors tumor progression due to enhanced pro-tumorigenic inflammation (96). |
1. Anti-CD200 Samalizumab: NCT03013998 |
| Lag-3 |
Lag-3 receptor of negative co-stimulation. Ligand: MHC II. Lag-3/MHCII signaling - tolerance maintenance (83, 97). |
Lag-3 signaling-suppression of CTL activity in tumors (97, 98). Blocking of PD-L1, CTLA-4 and Lag-3—effective and enduring immunotherapy for disseminated leukemia in murine model (98). |
To date—no clinical trials available |
| Tim-3 |
Tim-3—receptor of negative co-stimulation. Ligands: gal-9/HMGB1/phosphatidyl serin. Tim-3/gal-9 signaling—regulation of T-cell tolerance (83). |
Tim-3 released by AML—reduce ability of T cells to secrete IL-2 required for NK and CTLs activation (99). TIM-3 and PD-1 co-expression on T cells was associated with AML progression in mouse and human (7) and with relapse in AML patients after allo-SCT (100). TIM-3—overexpression on AML (stem) cells (101) and T cells of newly diagnosed AML -(102). Blocking of TIM-3 and PD-1—reduced tumor burden and improved survival in AML murine model (7). |
1. AntiPD-1
+
TIM-3 PDR001+MBG453+ Decitabine: NCT03066648 |
| IDO and Tregs |
IDO –immunosuppressive and tolerogenic enzyme responsible for tryptophan degradation in kynurenines with subsequent T cell inhibition and Tregs expansion. Tregs—role in maternal tolerance, autoimmune disease regulation, suppression of transplant rejection (85). |
IDO signaling—Tregs induced by IDO-expressing leukemic DCs impair leukemia-specific CTL (103).Increased IDO activity—lower CR rates and shorter OS in AML (103–105). Blocking of IDO—effective immune response in AML in vitro (103–106). |
1. Anti-IDO Epacadostat: NCT03444649 |
Different inhibitory pathways and their role in both physiological and AML contexts are correlated with clinical trials ongoing for specific pathways.