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. 2023 Nov 11;22:180. doi: 10.1186/s12943-023-01889-6

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