Table 2 Studies on treatment options addressing distinct immune escape mechanisms
References | Intervention | Rational | Study Population | Study Type | Best outcome | Toxicity | ||
Addressed mechanism: HLA downregulation | ||||||||
 Toffalori et al. [17] | Systemic IFNy production via induction of GvHD | Upregulation of MHC II molecules via IFNy | AML cell lines | Preclinical model | n.a | n.a | ||
 Gambacorta et al. [18] | EZH2-inhibitors (e.g. Tazemetostat) | Pharmacological PRC2 inhibition with upregulation of HLA II molecule (independent of IFNy) | AML cell lines | Preclinical model | n.a | n.a | ||
 Christopher et al. [16] | IFN-y | Upregulation of MHC II molecules | AML cell lines | Preclinical model | n.a | n.a | ||
 Rimando et al. [178] | Flotetuzumab (CD123xCD3 DART)/ CD123 CAR-T-cells | Upregulation of MCH II molecules via INFy production by CD4 + T-cells | AML cell lines and xenografts from relapsed/ refractory AML patients | Preclinical model based on samples from patients with AML relapse post allo-HCT enrolled in a Phase I/II trial | n.a | n.a | ||
 Uy et al. [173] | Flotetuzumab (CD123xCD3 DART) | Upregulation of MCH II molecules via INF-y production | 88 patients with r/r AML | Phase I/II trial | ORR 30% at the recommended Phase II dose (500 ng/kg) | Most common grade ≥ 3 AE were IRR/CRS (8%), cytopenias, hypophosphatemia, hypokalemia | ||
 Ho et al. [22] | MDM2-inhibition | MDM2-inhibition enhances T-cell mediated allogeneic immune response by upregulation of HLA-I and II molecules and increase of TRAIL-R1/2 on AML blasts | AML cell lines and xenografts | Preclinical model | n.a | n.a | ||
References | Intervention | Study Population | Study Type | Best outcome | Toxicity | |||
Addressed mechanism: HLA loss | ||||||||
 Crucitti et al. [38] | Donor change for allo-HCT2 | 23 patients with myeloid malignancies (AML, n = 20) relapse and HLA loss after allo-HCT | Retrospective study | Donor change associated with better survival (median OS 146 months vs 69 months) in HLA loss relapses, but not different from “classical relapses (152 vs 91 months) | Early transplant related mortality was high (41%) | |||
 Muniz et al. [32] | DLI/ second HCT | 6 patients with HLA loss (myeloid malignancies, n = 2, lymphoid, n = 4) | Retrospective study | 3 patients unsuccessfully treated with DLI (+ chemotherapy/ other drugs), 1 patient achieved CR for 18 months after allo-HCT2 from alternative donor but relapsed thereafter, 2 patients died of disease progression | All 3 Patients with DLI developed severe GvHD | |||
 Wang et al. [33] | DLI/ chemotherapy/ CAR-T | 40 patients with HLA loss (6 without overt relapse). Myeloid malignancies, n = 27 | Retrospective study | 3 received DLI: PD, 2 IFNα: PD, 5 received BSC. 20 patients received DLI, targeted therapies, chemotherapy, CAR-T-cells with unsuccessful results. 3 achieved CR after chemotherapy + azacytidine, sorafenib CAR-T-cells, respectively) 2-y OS of patients with HLA loss not different from classical relapses (33% vs 29%) | NRM was lower in HLA loss patients than those with classical relapses (p = 0.035) | |||
 Wu et al. [34] | DLI/ chemotherapy/ CAR-T/ second HCT | 54 patients with HLA loss (AML, n = 29, ALL, n = 25) | Retrospective study | Pre-emptive DLI in HLA loss (n = 14) vs classical relapses (n = 10) did not prevent relapse after MRD diagnosis Response rates after salvage therapy was similar in HLA loss and classical relapses (55% vs 45%) Allo-HCT2 was performed only in 2 patient2 with HLA loss | not reported | |||
References | Intervention | Rational | Study Population | Study Type | Best outcome | Toxicity | ||
Addressed mechanism: immune checkpoints | ||||||||
 Davids et al. [73] | CTLA-4 blockade (Ipilimumab) | Inhibition of CTLA-4 mediated T-cell inactivation | 28 patients with relapsed hematological neoplasia after allo-HCT (AML, n = 12) | Phase I trial | ORR 32% (best responses at 10 mg/kg (7/22), no responses at 3 mg/kg, n = 6). 3/3 with leukemia cutis achieved CR | DLT at 3 mg/kg: GvHD gut/liver 1/6, IrAE 2/6, DLT at 10 mg/kg: GvHD 3/22, IrAE Grade ≥ 2 4/22 (colitis, pneumonitis, hepatitis) | ||
 Davids et al. [176] | PD-1 blockade (Nivolumab) | Reversal of T-cell exhaustion | 28 patients with relapsed hematological neoplasia after allo-HCT (AML, n = 10, MDS = 7) | Phase I trial | ORR 32% (3/5 evaluable patients at 1 mg/kg, 5/20 at 0,5 mg/kg). No patient with eAML responder (n = 6) | DLT at 1 mg/kg 2/6 Sepsis, antiphospholipid syndrome) DLT at 0.5 mg/kg 4/22 (GvHD gut/liver, other liver toxicities) | ||
 Godfrey et al. [74] | PD-1 blockade (Pembrolizumab) | Reversal of T-cell exhaustion | 12 patients with relapsed hematological neoplasia after allo-HCT (AML, n = 8) | Phase I/II trial | ORR 22% at fix dose pembrolizumab 200 mg (lymphoid malignancies only) | IrAE Grade 3–4 5/12 hemolysis, thrombopenia, hypothyroidism, pneumonitis), no GvHD | ||
 Holderried et al. [177] | PD-1/ CTLA-4 blockade with or without DLI | Reversal of T-cell exhaustion | 21 patients with hematological malignancies other than Hodgkin lymphoma (AML/MDS, n = 12) | Retrospective study | ORR Nivolumab: 40%, Nivolumab plus DLI: 80%, Ipilimumab: 20% | Overall a/c GvHD: 48% (100% after Nivolumab plus DLI) Grade 3/4 aGvHD or moderate/extensive cGvHD: 29% (60% after Nivolumab plus DLI). IrAE were rare | ||
 Daver et al. [179] | PD-1 blockade (Nivolumab) + Azacytidine | Reversal of T-cell exhaustion/ inhibition of PDL-1 mediated resistance to Azacytidine | 13 patients with relapsed AML after allo-HCT | Phase II trial | ORR 23% (Nivolumab 3 mg/kg) | Not reported separately for post-HCT | ||
 Garcia et al. [180] | CTLA-4 blockade + Decitabine | Inhibition of CTLA-4 mediated T-cell inactivation | 25 patients with relapsed MDS/AML after allo-HCT | Phase I trial | ORR 20%, mostly at 10 mg/kg (3/6 with myeloid sarcoma achieved CR) | IrAE 44% (63% at Ipilimumab 10 mg/kg). No DLT at 3 and 5 mg/kg. 3 DLT at 10 mg/kg | ||
 Albring et al. [75] | PD-1 blockade (Nivolumab) | Reversal of T-cell exhaustion | 3 patients with AML relapse after allo-HCT | Case series | 2 patients with response (1 CR, 1 SD) | GvHD grades 3 and 2, respectively | ||
 Yao et al. [181] | PD-1 blockade (Tislelizumab) + Azacytidine | Reversal of T-cell exhaustion | 1 patient with AML relapse after allo-HCT | Case report | Complete molecular remission | Lethal GvHD | ||
 Wong et al. [182] | PD-1 blockade (Nivolumab) | Reversal of T-cell exhaustion | 1 patient with AML relapse after allo-HCT | Case report | Transient response (PR/SD) | No GvHD, IrAE suspected | ||
 Penter et al. [183] | PD-1 blockade (Nivolumab) | Reversal of T-cell exhaustion | 1 patient with AML relapse after allo-HCT | Case report | Transient response (PR/SD) | Not reported | ||
Addressed mechanism: Lactic acid-induced metabolic and functional T-cell inhibition | ||||||||
 Uhl et al. [130] | Sodium Bicarbonate (NaBi) | Reversal of LA-induced impairment of T-cell function | Murine and human AML cell lines; AML cells from 10 patients with relapsed AML after allo-HCT | Preclinical model | n.a | n.a | ||