Immunotherapy in Acute Myeloid Leukemia: A Literature Review of Emerging Strategies.

1. Introduction

In the last twenty years, the knowledge of mechanisms of leukemogenesis and molecular/genetic features of acute myeloid leukemia (AML) has rapidly progressed, allowing a precise characterization of the disease and several updates on AML classification [ 1 , 2 ]. In the same fashion, we have witnessed breakthroughs in drug development for myeloid neoplasms. For instance, the most illustrative case is the drug-free combination of all-trans retinoic acid/arsenic trioxide for acute promyelocytic leukemia (APL), capable of curing the disease in the vast majority of patients [ 3 , 4 ].

The introduction in clinical practice of new drugs, such as Gemtuzumab Ozogamicin, CPX 3-5-1, hypomethylating agents (HMA) and Venetoclax (VEN) [ 5 , 6 , 7 ], the efficient use of measurable residual disease [ 8 ] (MRD), the optimization of hematopoietic stem cell transplantation (HSCT) conditioning regimens [ 9 ], and the improvements of supportive therapy led to a paradigm shift in the management of AML, allowing a therapeutic path tailored to the inherent features of both disease and patients. However, except for APL and core-binding factor AML (CBF-AML), the outcome of AML patients remains dismal. According to the MD Anderson case series, the 5-year overall survival rate still does not reach 20%, despite having doubled since early 2000 [ 10 ].

Thus, the recent and successful introduction of immunotherapies, such as antibody-based therapy, checkpoint inhibitors, and chimeric antigen receptor (CAR) strategies, in lymphoid malignancies has raised hopes for their possible use in AML as well.

Furthermore, other immunologic therapies showed efficacy in AML, and some of them are established as gold standards in different settings. The most illustrative example is HSCT: after HSC engraftment, the donor immune system is capable of targeting the residual leukemic cells, giving life to the so-called “Graft-versus-Leukemia” (GvL) effect [ 11 ]. Key characters in this setting are lymphocytes, in particular CD4-CD25-FoxP3-positive regulatory T cells (Tregs), which have been proven to avoid alloreactive reactions, prevent reactions of the graft against the host (“Graft-versus-host-disease” effect, GvHD), and foster engraftment [ 12 ]. Other proofs of the immune effects of these cells come from high-resolution in vivo imaging studies, showing co-localization of HSCs with Tregs, proving thus a role in the creation of a permissing microenvironment [ 13 ], and the efficacy of donor lymphocyte infusion as adoptive immunotherapy for relapse after HSCT [ 14 ].

Also, other AML treatments present immunomodulatory effects: in preclinical models, Azacytidine (AZA) showed efficacy in preventing GvHD in combination with Tregs, which resulted in resistance to the antiproliferative activity of the drug [ 15 , 16 ]. Furthermore, analysis of bone marrows from patients enrolled in the RAS-AZIC trial suggested an AZA-dependent reconstitution of T-cell repertoires [ 17 ]. In a similar fashion, histone deacetylase inhibitors (HDACIs) enhance the production and suppressive functions of FOXP3(+) Tregs and stimulate tumor antigenicity and targeted immune system-mediated cytotoxicity in CD8+ T cells and NK cells [ 18 , 19 ]. These results were observed in a suppression of GVHD context while retaining beneficial GVL effects [ 20 ]. Sorafenib, a FLT3 inhibitor, through the downregulation of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7, enhances IL-15 transcription in FLT3 + AML cells, which causes an increase in CD8+CD107a+IFN-γ+ T cells and is capable of eradicating leukemia cells [ 21 ].

On the other hand, recent immunologic strategies, such as peptide and dendritic cell-based vaccines, didn’t show satisfactory results, especially in active disease settings. Although immunological activity was documented, most of the experiences reported a low rate of clinical responses [ 22 , 23 , 24 ], with the notable exception of the trial by Dong et al., who showed the efficacy of a combination therapy with low-dose chemotherapy and dendritic cell-based vaccines vs. chemotherapy alone in elderly patients [ 25 ]. The vaccine’s efficacy as maintenance therapy in post-chemotherapy and post-HSCT settings provided better results, prolonging survival and eradicating MRD [ 26 , 27 , 28 , 29 ]. Thus, several ongoing phase I and II clinical trials are investigating their potential role in this setting [ 30 ].

For a more comprehensive discussion of these topics, we refer to specialized reviews [ 30 , 31 ]. In this paper, we review the mechanisms underlying the main emerging immunotherapy strategies in AML, the results of the early clinical trials, and the new directions.

2. Antibody-Based Therapy

Antibody-based therapies enclose differently-structured molecules able to bind an effector cell to AML blasts in order to activate the immune response [ 32 ]. One successful example of this class of drugs is Blinatumomab, a paradigm-shifting bispecific T-cell engager (BiTE), which has first been shown to prolong survival in acute lymphoblastic leukemia (ALL) [ 33 ]. Bispecific antibodies used in cancer immunotherapy have dual affinities targeting both tumor and immune cells, engaging them and promoting effective antitumoral responses. BiTE antibodies possess two single-chain variable fragment (scFv) regions, each of them with light (VL) and heavy (VH) chains, from two different monoclonal antibodies able to bind a tumor-associated antigen and CD3 receptor in T cells [ 34 ] ( Figure 1 A). Subsequent variations of this construct are dual affinity retargeting antibodies (DARTs), characterized by an alternative link between VL and VH chains from the two antibodies and an additional interchain disulfide bond to improve stabilization [ 35 ] ( Figure 1 B); bispecific killer engager (BiKE), binding NK cells instead of T cells via CD16 ( Figure 1 C); and trispecific killer engager (TriKE), BiKE characterized by the incorporation of an IL-15 linker [ 36 ] ( Figure 1 D).

A common issue for both antibody-based therapy and CAR-T strategies is selecting the proper target in AML blasts since there are no antigens exclusively expressed by these cells. Illustratively, CD33 and CD123, targeted by the conjugate antibody Gemtuzumab Ozogamicin and the fusion protein Tagraxofusp, are also present on normal HSCs [ 37 ], while they are expressed in a high but submaximal rate (70–90%) of AML blasts. This may result, on the one hand, in an incomplete clearance of the blasts and, on the other hand, in harm to the healthy HSC compartment. In addition, there are side effects, both common to conventional AML management strategies, such as high rates of opportunistic and nosocomial infections due to cytopenia [ 38 , 39 , 40 ], and those related to specific targets, such as veno-occlusive disease, due to the expression of CD33 on hepatic Kupffer cells, observed also in patients treated with Gemtuzumab Ozogamicin [ 41 ], and cytokine release syndrome (CRS), due to activation of bystander immune cells and non-immune cells, such as endothelial cells, after binding the target antigen [ 42 ].

Both Gemtuzumab Ozogamicin and Tagraxofusp represented important breakthroughs in AML treatment: the first one was approved as first-line therapy in combination with daunorubicin and cytarabine in low-intermediate-risk de novo AML after the phase III ALFA-0701 trial and the metanalysis by Hills et al. [ 7 , 43 ], which showed a survival advantage in these subsets of patients vs. chemotherapy alone. Tagraxofusp was approved for the treatment of blastic plasmacytoid dendritic cell neoplasms (BPDCN) following the trial by Pemmaraju et al., which documented clinical responses in both de-novo and pre-treated patients [ 44 ]. Ongoing trials are investigating the efficacy of Tagraxofusp in other myeloid malignancies, including de novo and secondary AML [ 45 , 46 ].

The same targets (CD33 and CD123, respectively) were also used for most antibody-based strategies, as described in the next paragraphs.

2.1. T-Cell-Binding Antibodies

T-cell-binding strategies (e.g., BiTE and DARTs) have been tested in refractory/relapsed (R/R) AML patients in several phase I trials ( Table 1 ). The first BiTE data, of Flotetuzumab, a CD123 × CD3 DART, and AMG330, a CD33 × CD3 BiTE, were presented at the 2018 American Society of Hematology (ASH) meeting.

The first dose-escalation analysis of Flotetuzumab showed, in patients treated with the recommended Phase 2 dose (500 ng/kg per day administered as a continuous intravenous [IV] infusion), an overall response rate (ORR, including complete response [CR], complete response with incomplete count recovery [CRi, defined as platelet count < 100 × 10 9 /L and/or absolute neutrophil count < 1 × 10 9 /L], morphologic leukemia-free state [MLFS] and partial response [PR]) of 22% and a composite complete response (cCR, including CR, CRi, and MLFS) rate of 19%. Infusion-related reactions (IRR)/CRS occurred in all thirty patients treated (grade ≥ 3 in 13.3%) [ 47 ].

In 2021, the report of the dose expansion cohort was published. cCR rate was 20%, with an ORR of 24%. IRR/CRS were observed in 96% of patients (grade ≥ 3 in 4%). Grade ≥ 3 neutropenia and thrombocytopenia occurred in 2% and 6%, respectively [ 48 ]. A trial enrolling pediatric patients is currently ongoing ( NCT04158739 ). A clinical trial evaluating a second-generation CD123 × CD3 DART, MGD024, engineered to minimize CRS while maintaining antitumor activity, is ongoing as well ( NCT05362773 ).

The phase 1 dose escalation study evaluating AMG330 as a continuous IV infusion in patients with R/R AML showed a cCR rate of 11.4%, with an 89% treatment discontinuation rate for disease progression, adverse events, and/or patient requests. Grade ≥ 3 CRS was observed in 31.4% [ 49 ]. The study update in 2020 confirmed the low cCR rate (19%). CRS was observed in 67% of cases; ≥grade 3 in 13% [ 50 ].

In 2019, the results of AMG673, a CD33 × CD3 BiTE genetically fused to the N-terminus of a single-chain IgG Fc region (to increase the half-life of the molecule), phase I study were presented: an ORR of 22.2% with a cCR rate of 3.7% were observed. CRS occurred in 50% of patients (≥grade 3 in 13.3%) [ 51 ].

CD123 was also targeted by a BiTE, Vibecotamab; the phase I dose-escalation study, enrolling 104 AML, 1 B-cell ALL, and 1 chronic myeloid leukemia (CML), showed, at the higher dose tested (0.75 µg/kg), a cCR rate of 13.7%; CRS occurred in 58.5% of patients (8% grade ≥ 3) [ 52 ]. A phase II study was designed in order to investigate the potential role of Vibecotamab in AML patients in first or second morphological remission with detectable MRD and a cut-off expression of CD123 of ≥20% with the primary objective of obtaining MRD negativity [ 53 ].

A combination with conventional therapy was tested with a second CD123 × CD3 BiTE: APVO436. This drug was at first evaluated as monotherapy in relapsed/refractory (R/R) AML or MDS. In the AML cohort, 2 of the 34 evaluable patients (5.8%) obtained CR. Overall, IRR/CRS were observed in 50% of patients (≥grade 3 in 13%) [ 54 ]. An update of the study evaluating APVO436 as an adjunct to the standard of care was presented at the 2022 ASH meeting. The cCR rate was 20% as monotherapy, 40% in combination with Azacitidine (AZA) and VEN, and 33% in combination with Mitoxantrone, Etoposide, and Cytarabine (MEC) chemotherapy. IRR/CRS were observed in 30% of patients (≥grade 3 in 3.3%) [ 55 ].

Recently, new antigen targets are being explored in ongoing clinical trials: Tepoditamab (MCLA-117), a BiTE targeting CD3, and CLEC12A, an antigen present on leukemic stem cells and leukemic blasts whose expression seems stable throughout diagnosis, treatment, and relapse [ 56 ], showed, as early clinical results, an ORR of 10.3% with a MLFS rate of 1.7% and a CRS rate of 36.2% (≥grade 3 in 8.6%) [ 57 ]; and CLN-049, a FLT3 × CD3 BiTE, which showed high efficacy against human leukemic cell lines and patient-derived AML in mouse xenograft models [ 58 ]. No clinical results are currently available ( NCT05143996 ).

2.2. NK-Cell-Binding Antibodies

Since the early 2010s, efforts have been made to redirect NK-cell activity against AML blasts. In 2013, Wiernick et al. observed that CD16 × 33 BiKE and ADAM17 inhibitors can overcome inhibitory signals mediated by class I major histocompatibility complex (MHC) recognition and CD16 clipping, resulting in potent NK cell killing of CD33+ AML targets [ 59 ]. In the same fashion, Gleason et al. documented a significantly enhanced activation and degranulation of CD16 × CD33 BiKE-induced NK in myelodysplastic syndrome (MDS) cells, irrespective of disease stage and karyotype features [ 60 ].

More recently, the role of CD16 × CD33 BiKE was investigated in pediatric CD33+ AML and ALL patients. NK cells from the patients profited from restoration of effector functions by BiKE treatment, which, thus, could constitute a promising new option for supporting maintenance therapy or “bridging” consolidation chemotherapy before HSCT [ 61 ]. The only clinical results from this class of drugs come from the dose-finding study of GTB-3550, a CD16/IL-15/CD33 TriKE tested in R/R AML and R/R high-risk MDS, presented at the 2020 ASH meeting. These early data in 4 patients did not show an objective response, but NK proliferation and activation were observed [ 62 ]. A second report, in 2021, described a 25% ORR without any CR [ 63 ] ( Table 1 ). bioengineering-10-01228-t001_Table 1 Table 1 Results from clinical trials in relapsed/refractory AML-antibody-based therapies. Drug (Phase of the Study) Structure Outcome Year Reference Flotetuzumab (Phase I) AntiCD3 × CD123 DART ORR 22%, cCR 19% 2018 [ 47 ] GTB-3550 (Phase I, dose escalation) CD16/IL-15/CD33 TriKE No Response 2018 [ 62 ] AMG673 (Phase I, dose escalation) AntiCD3 × CD33 BiTE ORR 22.2%, cCR 3.7% 2019 [ 51 ] AMG330 (Phase I, dose escalation) AntiCD3 × CD33 BiTE cCR 19% 2020 [ 50 ] Vibecotamab (Phase I, dose escalation) AntiCD3 × CD123 BiTE cCR 13.7% 2020 [ 52 ] Tepoditamab (Phase I, dose escalation) AntiCD3 × CLEC12A BiTE ORR 10.3% cCR 1.7% 2020 [ 57 ] APVO436 (Phase I, dose escalation) AntiCD3 × CD123 BiTE CR 5.8% 2021 [ 54 ] Flotetuzumab (Phase I/II) AntiCD3 × CD123 DART ORR 24%, cCR 20% 2021 [ 48 ] GTB-3550 (Phase I) CD16/IL-15/CD33 TriKE ORR 25% 2021 [ 63 ] APVO436 (Phase I) AntiCD3 × CD123 BiTE cCR 20% (monotherapy) cCR 33% (+MEC chemotherapy) cCR40% (+AZA/VEN) 2022 [ 55 ]

3. Chimeric Antigen Receptor Strategies

CAR-T cells are constructs composed of an antigen recognition extracellular domain, a transmembrane domain, and an intracellular domain consisting of a co-stimulation domain and cluster of differentiation 3 (CD3 ζ signaling tail) [ 64 ] ( Figure 2 ). The variable region of monoclonal antibodies able to bind a target antigen is used as the source for the antigen recognition extracellular domain, which consists of a scFv fragment, VL, and VH chains linked together with short linker peptides of serine-glycine or glutamate–lysine [ 65 ]. This novel therapy represented a massive breakthrough in lymphoid malignancies, establishing it as a salvage treatment in ALL, lymphomas, and multiple myeloma [ 66 ]. As mentioned above, the path to CAR-T in AML has been rough, but the latest results from the clinical trials provided promising results ( Table 2 ).

3.1. CAR-T

The first clinical trial published in 2015, testing a CD33-directed CAR-T, enrolled one R/R AML patient. A decrease in blasts was observed without a clinical response; furthermore, IRR occurred [ 67 ].

In 2019, a CAR-T directed against NKG2D (Natural Killer Group 2, Member D), a receptor that transmits activation signals in NK-cells and activates the immune system against NKG2D ligands, expressed in AML blasts and poorly expressed in healthy tissues [ 68 ], was tested in seven R/R AML patients. In the same fashion, although a transient improvement of hematologic parameters in one patient was documented, no objective response was observed. No CRS occurred [ 69 ].

In 2021, a new trial evaluated a CD33-directed CAR-T in 3 patients; again, none of them met criteria for response to treatment. Two patients developed CRS [ 70 ].

In the same year, one case of a CD38+ AML refractory to chemotherapy combined with an anti-CD38 monoclonal antibody (Daratumumab) successfully treated with CD38-directed CAR-T was reported [ 71 ]. Although the efficacy was reported in one case, subsequent studies on CART-38 in AML patient-derived xenograft models confirmed the anti-leukemic activity [ 72 ]. A CD38-directed CAR-T trial is currently ongoing ( NCT04351022 ).

In the 2022 ASH meeting, several encouraging new data were presented.

PRGN-3006, a CD33-directed CAR-T with IL-15 membrane bound, was tested in 20 R/R AML, 1 chronic myelomonocytic leukemia (CMML) with ≥5% blasts, and 3 high-risk MDS without (cohort 1) or with lymphodepletion (fludarabine 30 mg/m 2 and cyclophosphamide 500 mg/m 2 days −5 to −3; cohort 2). No response was observed in cohort 1; among the 10 AML patients enrolled in cohort 2, the cCR rate was 20% with an ORR of 30%. Overall, CRS occurred in 70.8% of patients (≥grade 3 in 4.2%) [ 73 ].

UCART123v1.2, an universal, anti-CD123 allogeneic CAR-T product obtained by the ex vivo knockout of the genes of the T-cell receptor (TCR) alpha constant and CD52 to minimize the risk of GvHD and allow the use of anti-CD52-directed therapy as part of lymphodepletion, was tested in combination with Alemtuzumab (anti-CD52) in 16 patients: 1 patient (6.2%) achieved MLFS, and 1 patient had MRD-negative CR. CRS occurred in 93.7% of patients (≥grade 3 in 18.7%) [ 74 ].

An anti-CD123 CAR-T was also tested in 12 R/R AML pediatric patients in a phase I dose escalation trial; the ORR was 16.7%, with one patient (8.3%) achieving CR. No CRS occurred [ 75 ].

In 2020, the first case of successful CAR-T targeting CLL1 (also named CLEC12A), also targeted by bispecific antibody-based strategies (see above), was reported in a patient with secondary AML [ 76 ]. In 2022, anti-CLL1 CAR-T was tested in 10 R/R AML patients with a cCR rate of 70%; furthermore, 6 patients obtained MRD-CR (transient in 4 cases), and 6 patients underwent HSCT. All patients developed CRS; only one patient presented grade ≥ 3 neutropenia [ 77 ].

CLL1 was also successfully targeted in the pediatric population; in 2021, a phase I interim analysis showed an ORR of 81.8% with a cCR rate of 72.7% (50% achieving MRD negativity) [ 78 ]. In 2022, the phase I/II study confirmed the promising results: 4 out of 8 recruited patients achieved MRD-negative MLFS, 1 patient had MLFS and MRD positivity, 1 patient had CRi and MRD positivity, 1 patient had PR, and 1 patient remained at stable disease (SD) status but had CLL1-positive AML blast clearance [ 79 ].

Recently, anti-CLL1 CAR-T with stimulatory domains was tested: 4 patients were treated with CD28/CD27-equipped anti-CLL1 CAR-T, while 3 were treated with 4-1-BB-equipped anti-CLL1 CAR-T. In the first group, 3/4 patients achieved MRD-negative CR, while in the second one, 1 pt achieved MRD-positive CR and one pt achieved MRD-negative CR; CRS was experienced by all patients without ≥grade 3 events [ 80 ].

Other CLL1-directed CAR-T trials are currently ongoing ( NCT04219163 , NCT04884984 , and NCT04923919 ).

3.2. CAR-NK

To date, early results from only one trial testing CAR-NK in R/R AML patients have been presented.

An anti-CD33 CAR-NK was tested in 10 heavily pre-treated patients (median of lines: 5, range: 3 to 8) in a phase I dose escalation trial (6 × 10 8 , 1.2 × 10 9 , or 1.8 × 10 9 cells per round after the precondition with Fludarabine (30 mg/m 2 ) and Cytoxan 300–500 mg/m 2 for 3 days to 5 days, determined by tumor burden at baseline).

An MRD-negative CR rate of 60% was achieved. CRS was observed in 70% of patients without ≥grade 3 events [ 81 ]. Three clinical trials testing NKG2D-directed CAR-NK are currently ongoing ( NCT04167696 , NCT04658004 , and NCT04623944 ). bioengineering-10-01228-t002_Table 2 Table 2 Results from clinical trials in relapsed/refractory AML—CAR-T. Drug (Phase of the Study) Structure Outcome Year Reference CD33-CAR-T (Phase I) CAR-T × CD33 No response * 2015 [ 67 ] NKG2D-CAR-T (Phase I) CAR-T × NKG2D No response 2019 [ 69 ] CD33-CAR-T (Phase I) CAR-T × CD33 No response 2021 [ 70 ] CAR-T-38 (Phase I) CAR-T × CD38 ORR 100% * 2021 [ 71 ] CAR-T-CLL1 (Phase I) CAR-T × CLL1 ORR 81.8% cCR 72.7% ** 2021 [ 78 ] PRGN-3006 (Phase I, dose escalation) CAR-T × CD33, Il-15 bound ORR 0% in non-lymphodepleting cohort ORR 30% cCR 20% in lymphodepleting cohort 2022 [ 73 ] CAR-T-123 (Phase I, dose escalation) CAR-T × CD123 ORR 16.7% CR 8.3% ** 2022 [ 75 ] CAR-T-CLL1 (Phase I) CAR-T × CLL1 cCR 70% 2022 [ 77 ] CAR-T-CLL1 (Phase I/II) CAR-T × CLL1 ORR 87.5% cCR 75% ** 2022 [ 79 ] UCART123v1.2 + Alemtuzumab (Phase I, dose escalation) CAR-T × CD123 cCR 12.5% 2022 [ 74 ] CD33-CAR-NK + Fludarabine/Cyclophosphamide (Phase I, dose escalation) CAR-NK × CD33 MRD-CR 60% 2022 [ 81 ] CAR-T-CLL1 (Phase I) 4-1-BB CAR-T × CLL1 CD28/CD27 CAR-T × CLL1 CR 67% ** CR 75% ** 2023 [ 80 ] * One patient was enrolled in the trial. ** Trials enrolling pediatric patients.

3.3. Future Directions

Ongoing clinical trials are exploring new targets, such as: CD7 ( NCT04762485 , NCT04033302 ), whose targeted CAR-T was able to efficiently kill CD7+ AML cells and CD7+ primary blasts of R/R-AML patients in vitro and significantly inhibit leukemia cell growth in a xenograft mouse model [ 82 ]; CD19 ( NCT04257175 ), occasionally expressed in AML blasts (especially in CBF-AML) [ 83 ]; CD44v6 ( NCT04097301 ), overexpressed in FLT3 and DNMT3A -mutated AML and already successfully targeted by CAR-T constructs in pre-clinical studies [ 84 ]; CD70 ( NCT04662294 ), expressed on most leukemic blasts but with little or no expression in normal bone marrow samples, is already targeted by the human monoclonal antibody Casatuzumab [ 85 ]; FLT3 ( NCT05023707 , NCT03904069 , NCT05017883 ), whose targeted CAR-T showed potent inhibition of leukemia proliferation in xenograft models [ 86 ]; LILRB4 (alias ILT3) ( NCT04803929 ), highly expressed in AML with monocytic differentiation and suspected to be involved in tumor escape, maintains an immunosuppressive milieu for tumor cells [ 87 ]; CD276 ( NCT04692948 ), expressed in AML with monocytic differentiation as well, whose targeted CAR-T exhibited efficient antigen-dependent cytotoxicity in vitro and in xenograft models of AML [ 88 ].

4. Checkpoint Inhibitors

The comprehensive knowledge of tumor microenvironment and mechanisms of therapy escape led to the development, since the early 2010s, of drugs targeting the broad landscape of cells and molecules around the tumor cells, first in solid tumors than in hematologic malignancies [ 89 ]. In a similar fashion as the other immunotherapies, also for checkpoint inhibitors, lymphoproliferative diseases were the first ones to be successfully treated with this class of drugs [ 90 ], while in AML, the results from the clinical trial are less convincing (see Table 3 ), and the optimal therapy combination and clinical setting are still matters of debate.

4.1. SIRP/CD47 Pathway

CD47 is a transmembrane protein broadly expressed in human cells and on many types of tumors, where it plays a pivotal role in immune escape; in fact, the binding to its ligand, SIRPα (thrombospondin-1 and signal regulatory protein α), triggers a “don’t eat me” signal to the macrophages, inhibiting phagocytosis [ 91 ]. In the same fashion, CD47 expression promotes survival by preventing dendritic cell-mediated T-cell necroptosis ( Figure 3 ) [ 92 ].

In AML, CD47 is overexpressed and correlates with a poor prognosis [ 93 , 94 ]. Majeti et al. showed that blocking monoclonal antibodies directed against CD47 enabled phagocytosis of AML stem cells and inhibited their engraftment in vivo [ 93 ]. In a similar way, Jaiswal et al. documented minimal engraftment of AML cells expressing low levels of CD47 in immunodeficient mice; the same cells reached engraftment levels equivalent to those of CD47 high-expressing cells when macrophages were targeted with a SIRPα blocking antibody [ 95 ].

A second T cell-dependent mechanism in vivo was documented by Tseng et al., who showed that treatment with an anti-CD47 antibody had a greater effect in wild-type mice with established tumors than in T cell-deficient nude mice with equivalent tumor burden [ 96 ].

The first drug targeting SIRP/CD47 interaction was CC-90002, an anti-CD47 monoclonal antibody, whose results were presented in 2019: among the 24 R/R AML patients and 4 high-risk (HR) R/R MDS patients treated, no objective response was documented, with an 82% rate of treatment-emergent adverse events [ 97 ].

In the same year, the first results of another anti-CD47 antibody, Magrolimab, in combination with AZA were presented. 25 newly diagnosed (ND) AML patients ineligible for induction chemotherapy were enrolled; among the 16 patients evaluable for response, 11 obtained an objective response (9 cCR, 2 PR), and 5 presented stable disease. Interestingly, 5/6 TP53 -mutated AML patients achieved cCR. The combination therapy was well tolerated, with a safety profile similar to AZA monotherapy [ 98 ].

The 2021 update of the study confirmed the promising results, with a 65% ORR (44% CR, 12% CRi, and 6% MLFS); in the subset of TP53 -mutated AML, the ORR was 71% (48% CR, 19% CRi, and 5% MLFS) [ 99 ]. A phase III trial evaluating Magrolimab plus AZA vs. the physician’s choice of AZA/VEN or intensive chemotherapy in TP53-mutated ND AML (ENHANCE-2 study, NCT04778397 ) is ongoing.

Surprisingly, the ENHANCE study, testing Magrolimab plus AZA in HR-MDS, was recently discontinued due to futility based on a planned analysis [ 100 ]; these results are not currently available.

A trial testing Magrolimab plus Atezolizumab (anti-programmed cell death 1 ligand 1 [PDL1]; see the following chapter) combination therapy ( NCT03922477 ) is ongoing.

Lemzoparlimab is an anti-CD47 antibody endowed with a red blood cell (RBC) sparing property and unique binding epitope, potentially differentiating itself from other CD47 axis-targeting therapies. Preliminary results from the phase I study, presented in 2020, showed a 20% cCR rate (MLFS) with an acceptable safety profile (no patient developed a treatment-related serious adverse event) [ 101 ]. The phase II study, along with a phase III study testing Lemzoparlimab in combination with AZA for HR MDS ( NCT05709093 ), are currently ongoing.

In 2022, Evorpacept, a fusion protein containing two engineered high-affinity CD47 binding domains of SIRPα linked to an inactive Fc region of human immunoglobulin was designed to promote the phagocytosis of tumor cells and was tested in combination with VEN and AZA in R/R AML or ND HR AML. A blast decrease was observed in all patients, with an objective response in all ND AML patients and 44.4% of R/R AML patients. Among the 14 patients enrolled, 1 grade 3 CRS occurred [ 102 ].

4.2. PD1/PDL1 Pathway

Programmed cell death protein 1 (PD1) is a cell surface receptor expressed on several types of T cells (Tregs, T-helper, and T-effectors) and other immune cells (B cells, NK cells) and has a fundamental role in countering positive signals through the TCR and CD28 by engaging its ligands PDL1 and/or PDL2 [ 103 ]. Thus, signals through the PD1 pathway contribute to regulation of T cell activation and functions, T cell tolerance, and return to immune homeostasis [ 104 , 105 ]. High and sustained expression of PD1 and its ligands is common in various types of cancer, representing a mechanism of immune escape [ 106 ]. Multiple evidence has highlighted an upregulation of the PD1/PDL1 pathway in AML and a correlation with poor overall survival, adverse-risk mutations and karyotype anomalies, and a higher relapse rate [ 107 , 108 , 109 , 110 ].

Several drugs targeting this pathway, blocking PD1 (Nivolumab, Pembrolizumab, and Cemiplimab) or PDL1 (Atezolizumab, Avelumab, and Durvalumab), have been successfully tested and approved by the FDA in solid cancers and hematologic malignancies [ 89 , 111 ], although none of these have been approved for AML.

The first data on Nivolumab in combination with AZA dates back to 2017; the early results, on 53 R/R AML patients, showed an ORR of 35% with a cCR rate of 14%. Furthermore, the median overall survival (5.7 months) was superior to historical survival with AZA-based salvage protocols from the same institution. ≥grade 3 immune-related adverse events (IrAE) were observed in 14% of patients and responded rapidly to steroids [ 112 ].

In the same year, the results of the therapy combination with Cytarabine and Idarubicin as first-line therapy in a cohort of ND AML and HR MDS (30 patients with AML 2 with HR MDS) were presented: the cCR rate was 72%. More than grade 3 IrAE occurred in 5 patients [ 113 ]. The final results were published in 2019: 44 patients were enrolled (42 patients had AML, 2 had HR MDS, and 4 patients did not receive Nivolumab), and the ORR was 77.2%; at a median follow-up of 17.25 months, the median overall survival was 18.5 months, and the median event-free survival was not reached. Response was consistent across second- and therapy-related AMLs, whereas the TP53 mutation was more frequent in non-responders ( p = 0.06). Six patients had seven grade 3–4 IrAEs with an overall acceptable safety profile [ 114 ].

Nivolumab was also tested as maintenance therapy. In 2018, it was tested in 14 patients with HR AML (adverse-risk cytogenetics, adverse-risk mutations, MRD+, second remission, therapy-related AML) in CR, with a 6 and 12 month CR duration of 79% and 71%, respectively. Five patents experienced ≥grade 3 IrAE [ 115 ]. In 2022, the results of a phase II single-arm trial testing Nivolumab as maintenance therapy in HR AML ineligible for HSCT were published: 15 patients (14 cCR, 1 PR) were enrolled, showing a 6-month relapse-free survival of 57.1% and ≥grade 3 IrAE rates of 26.7% [ 116 ]. The results of the REMAIN trial, presented at the 2022 ASH meeting, confirmed the suboptimal results: 80 patients with AML in cCR who were not candidates for HSCT were randomized between maintenance therapy with Nivolumab and observation; maintenance therapy failed to improve overall survival and progression-free survival [ 117 ].

In a similar fashion, Pembrolizumab was tested in different clinical settings: the combination with AZA was investigated in R/R AML and older ND AML by Gojo et al., who presented the preliminary results at the 2019 ASH meeting. The R/R AML cohort achieved an ORR of 17.2% (cCR 13.8%), while the ND AML cohort achieved 58.8% (cCR 47%). Grade 3/4 IrAE was observed in 9 (24%) patients in the first cohort and 3 (14%) patients in the second one [ 118 ].

The combination with Decitabine (DEC) was tested in a cohort of 10 R/R AML patients, of whom 3 obtained cCR. The toxicity profile of the combination therapy was consistent with that expected from DEC alone, with the exception of three patients who suffered IrAE, likely as a consequence of Pembrolizumab [ 119 ].

The combination with chemotherapy was explored in R/R patients by Zeidner et al.: 37 patients were enrolled to receive Pembrolizumab after high-dose cytarabine in a phase II study. The ORR was 46%, with a cCR rate of 38%; the administration of Pembrolizumab was associated with 5 IrAE, and no severe toxicity or delay in hematologic recovery were observed [ 120 ]. In a follow-up study, 9 patients undergoing alloSCT were compared with a historical control group of 18 AML patients who underwent alloSCT without prior Pembrolizumab exposure. One-year survival was not significantly different between the treatment groups, whereas 100-day mortality was 0% in the Pembrolizumab group versus 17% in the control group, and there was no increase in grade III-IV acute graft-versus-host disease (GVHD) in patients treated with pembrolizumab prior to alloSCT. No chronic GVHD was seen in patients treated with pembrolizumab prior to alloSCT [ 121 ].

Finally, Pembrolizumab was tested as maintenance therapy after autologous HSCT in non-favorable-risk AML patients in the first CR or beyond who were ineligible for alloSCT. Among the twenty patients enrolled, after a median follow-up of 80 months, 14 patients remain alive, with 10 in continuous remission. Treatment was well tolerated, with only 1 non-relapse death [ 122 ].

In 2022 the results of a large randomized phase II trial evaluating older patients with AML receiving AZA with or without Darvalumab were published. Although the therapy combination did not raise safety concerns, it failed to achieve a better response (ORR 31.3% vs. 35.4%, median overall survival 13 months vs. 14.4 months) [ 123 ].

Trials testing anti-PDL1 are currently ongoing ( NCT02953561 , NCT03395973, NCT02935361 , NCT02892318 , and NCT315482); no results are available at the moment.

4.3. TIM3/GAL-9 Pathway

T cell immunoglobulin and mucin domain 3 (TIM3) is a transmembrane protein expressed on immune cells (T cells, NK cells, and dendritic cells) that binds multiple ligands. One of the most known is Galectin-9 (β-Galactoside-binding lectin 9), which plays an important role in immune cell regulation. Zhu et al. showed that Gal-9, through the TIM3 link, was able to induce intracellular calcium flux, aggregation, and death of T helper cells, and administration of Gal-9 in vivo resulted in selective loss of interferon-gamma-producing cells [ 124 ]. In the same fashion, Ndhlovu et al. documented TIM3-dependent negative regulation in NK cells [ 125 ], and a higher suppressive function of TIM3+ Treg vs. TIM3-Tregs was observed in the tumor microenvironment [ 126 ].

The detection of TIM3 in myeloid malignancies cells, in particular MDS [ 127 ] and AML leukemic stem cells [ 128 ], along with the discovery of the prognostic negative significance of its overexpression in T cells [ 129 , 130 , 131 , 132 ], led to the development of drugs targeting this pathway. Darwish et al. showed that blocking TIM-3 in AML cell lines inhibited cell proliferation [ 133 ], whereas Kikushige et al. observed in mice models that anti-TIM3 antibody did not harm reconstitution of normal human HSCs but blocked engraftment of AML after xenotransplantation [ 134 ].

The first anti-TIM3 antibody, Sabatolimab, was tested in combination with HMA in a cohort of ND or R/R AML patients. The combination Sabatolimab plus DEC achieved an ORR of 41% in ND AML patients and 25% in R/R AML patients, whereas Sabatolimab plus AZA, tested only in ND AML patients, obtained a 27% ORR. Three IrAE were observed in the DEC cohort vs. none in the AZA cohort [ 135 ].

In the study update in 2021, in a cohort of 40 evaluable patients with ND AML, the ORR was 40.0%. The response rate was consistent in AML patients bearing an adverse-risk mutation (TP53/RUNX1/ASXL1; ORR: 53.8%). The combination was safe and well tolerated, with grade ≥ 3 adverse events similar to HMA alone [ 136 ].

Trials evaluating new clinical settings, such as AML in MRD+ CR after HSCT ( NCT04623216 ), and therapy combinations, such as Sabatolimab plus AZA/VEN (STIMULUS-AML1, NCT04150029 ), are currently ongoing.

4.4. CD27/CD70 Pathway

CD70 is a molecule expressed in activated T cells and dendritic cells that, by binding its ligand, CD27, a costimulatory receptor of the tumor necrosis factor superfamily, constitutively expressed on lymphocytes and hematologic stem cells, promotes lymphocyte expansion and cell survival [ 137 , 138 ]. Furthermore, CD70 is also aberrantly expressed by various malignancies, including AML blasts, where it promotes proliferation via the WTN pathway [ 138 ].

Thus, as also briefly discussed earlier, the CD27/70 pathway represents a good target to address AML; in fact, Riether et al., in in vitro studies, documented strong proliferation inhibition blocking CD27 and CD70 [ 138 ].

Casatuzumab, an anti-CD70, has been tested in combination with AZA in ND AML patients ineligible for chemotherapy in a phase I/II trial. The ORR in patients treated at the phase II dose was 37.9% (all in cCR). Seven patients (18.4%) reported infusion-related reactions, including two with grade 3 events. There were 10 fatal treatment-emergent adverse events; none were considered drug-related [ 139 ].

In 2021, the preliminary results of the therapy combination Cusatuzumab plus AZA/VEN in ND AML patients ineligible for chemotherapy were presented: among the evaluable 42 patients, the ORR was 92.9% (CR 47.6%, CRi 57.1%, MLFS 11.9%). Apart from the IrAE (11.4% of patients with 2.3% at grade ≥ 3), the safety profile was consistent with that previously reported for the AZA/VEN regimen [ 140 ].

4.5. CTLA4/CD80-86 Pathway

CTLA4 (cytotoxic T-lymphocyte-associated protein 4) is a transmembrane protein member of the immunoglobulin gene superfamily expressed by both CD4+ and CD8+ T cells, which, interacting with its ligands, CD80 and CD86, inhibits immune response [ 141 ]. Interestingly, CTLA4 is also expressed in AML blast, and its co-expression with PD1 correlates with a poor prognosis [ 142 ]. In fact, preclinical studies showed that antibody-based CTLA4 blockade results in an enhancement of the number and activity of T cells with an anti-leukemic effect [ 143 ].

Ipilimumab, an anti-CTLA4 antibody, was first tested as post-HSCT salvage therapy in various malignancies, including 2 AML patients; no effect was observed [ 144 ]. In 2023, Ipilimumab was tested in combination with DEC in 48 patients, split in two cohorts: 25 post-HSCT patients (23 AML and 2 MDS; all R/R) and 23 transplant-naïve patients (15 AML and 8 MDS; including 20 R/R and 3 previously untreated). The cCR rate in the first cohort was 20%, while in the second it was 56.5%. The overall IrAE rate was 44% (11 of 25) in the post-HSCT and 48% (11 of 23) in the transplant-naïve settings [ 145 ].

A phase I trial investigating Ipilimumab in combination with donor lymphocyte infusion (DLI) for myeloid malignancies relapsed after HSCT is ongoing ( NCT03912064 ). bioengineering-10-01228-t003_Table 3 Table 3 Results from clinical trials of acute myeloid leukemia checkpoint inhibitors. Drug (Phase of the Study) Target Population Outcome Year Reference Nivolumab + AZA (Phase Ib/II) Anti-PD1 53 R/R AML ORR 35% cCR 21% 2017 [ 112 ] CC-90002 (Phase I) Anti-CD47 24 R/R AML 4 R/R HR MDS No Response 2019 [ 97 ] Nivolumab + Cytarabine + Idarubicine (Phase II) Anti-PD1 42 ND AML 2 HR MDS ORR 77.2% 2019 [ 114 ] Pembrolizumab + AZA (Phase II) Anti-PD1 37 R/R AML 22 ND AML ORR 17.2% cCR 13.8% ORR 58.8% cCR 47% 2019 [ 118 ] Magrolimab + AZA (Phase I) Anti-CD47 25 ND AML ORR 69% cCR 56% 2019 [ 98 ] Lemzoparlimab (Phase I) Anti-CD47 5 R/R AML MLFS 20% 2020 [ 101 ] Sabatolimab + HMA (Phase I) Anti-TIM3 50 ND or R/R AML ORR 41% (DEC) ORR 27% (AZA) ORR 25% (DEC) 2020 [ 135 ] Pembrolizumab + Cytarabine (Phase II) Anti-PD1 37 R/R ORR 46% cCR 38% 2021 [ 120 ] Sabatolimab + HMA (Phase I/Ib) Anti-TIM3 48 ND AML ORR 40% 2021 [ 136 ] Magrolimab + AZA (Phase I) Anti-CD47 52 ND AML ORR 65% cCR 62% 2021 [ 99 ] Cusatuzumab + AZA/VEN (Phase I) Anti-CD70 44 ND AML cCR 92.9% 2021 [ 140 ] Evorpacept + AZA/VEN (Phase I) Anti-CD47 11 R/R AML 3 ND HR AML ORR 44.4% ORR 100% 2022 [ 102 ] Pembrolizumab + DEC (Phase II) Anti-PD1 10 R/R AML cCR 30% 2022 [ 119 ] AZA ± Darvalumab (Phase II) Anti-PD1 129 ND AML randomized to receive AZA with or without Darvalumab ORR 31.3% vs. 35.4% 2022 [ 123 ] Cusatuzumab + AZA (Phase I/II) Anti-CD70 38 ND AML cCR 37.9% 2023 [ 139 ] Ipilimumab + DEC (Phase I) Anti-CTLA4 25 postHSCT (23 R/R AML, 2 R/R MDS) 23 HSCT naive (15 AML, 8 MDS; 20 R/R 3 ND) cCR 20% cCR 56.5% 2023 [ 145 ]

4.6. Other Immune Checkpoint Targets

CD200 is a cell membrane glycoprotein of the immunoglobulin supergene family, present on both cells of myeloid/lymphoid origin. Its receptor, CD200R, is expressed on cells of the monocyte/myeloid lineage and some T-cell subsets [ 146 ]. CD200/CD200R is an important pathway in immune regulation, and the aberrant expression of CD200 on AML blasts is an efficient mechanism of immune evasion through Tregs expansion and NK cell function suppression [ 147 , 148 ]. On a clinical basis, this translates to a high risk of relapse and an inferior outcome [ 149 , 150 , 151 ]. In vitro and in vivo studies proved the efficacy and feasibility of targeting this axis in AML [ 152 , 153 ]. A trial testing multiple drugs, including Samalizumab, an anti-CD200 antibody, is currently ongoing (multi-study “Master Protocol [BAML-16-001-M1]”, NCT 03013998 ).

LAG-3 (lymphocyte activation gene-3) is a type I transmembrane protein with four Ig-like domains structurally similar to CD4 expressed on activated T cells. The bind with its ligand, MHC II, leads to the inhibition of T-cell functions; in fact, its blockade has been demonstrated to reinvigorate exhausted T cells and strengthen anti-infection immunity [ 154 ]. Multiple evidence has shown an overexpression of LAG-3 in T cells in AML [ 142 , 155 , 156 ]. To address this potential mechanism of immune escape, an ongoing trial is evaluating the therapy combination of Relatlimab, an anti-LAG-3 antibody, with Nivolumab or AZA in R/R AML patients. No results are currently available.

5. Conclusions

Immunotherapy is based on mechanisms of immune escape and responsiveness. Such mechanisms can be different in the pre-leukemic and transforming stages of diverse subsets of leukemia. Failure to receive immunotherapy can be triggered by diverse disease etiologies and by chemotherapy resistance and immune evasion. Furthermore, the complex and disease-specific microenvironment may contribute significantly to the differency in efficacy observed between AML and lymphoid disorders [ 12 ]. In this regard, the combination of immunotherapies and compounds targeting the leukemic niche could overcome therapy escape [ 157 ].

Given the genetic and epigenetic heterogeneity of pediatric and adult AML, immunotherapy has still not provided a paradigm-shifting breakthrough. The accumulation of genetic mutations and alterations of pathways defining anti-tumor activity are also very different across subsets of leukemia, which might explain different levels of response.

However, the safety profile has been good for most of the new drugs, and the therapy was well tolerated by patients, who were commonly elderly and subjected to a heavy previous burden of therapy. In addition, IrAEs were usually low-grade and easily treated with steroid therapy.

Concerning the anti-leukemic activity, some compounds showed encouraging results, but, unfortunately, there are still only a few randomized comparative studies, which are warranted to clarify the actual benefits and to frame these strategies in the most appropriate clinical subsets.

The ongoing trials evaluating drugs targeting new markers and addressing different patient subsets allow us to envision the possibility, for immunotherapies, of expanding both safe chemo-free strategies and first-line combination therapies in AML.

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Author Contributions

Conceptualization, L.G. Writing, L.G., C.B.-P. and V.V. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

References

1. Vardiman J.W. Harris N.L. Brunning R.D. The World Health Organization (WHO) classification of the myeloid neoplasms Blood 2002 100 2292 2302 10.1182/blood-2002-04-1199 12239137

2. Khoury J.D. Solary E. Abla O. Akkari Y. Alaggio R. Apperley J.F. Bejar R. Berti E. Busque L. Chan J.K.C. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms Leukemia 2022 36 1703 1719 10.1038/s41375-022-01613-1 35732831 PMC9252913

3. Lo-Coco F. Avvisati G. Vignetti M. Thiede C. Orlando S.M. Iacobelli S. Ferrara F. Fazi P. Cicconi L. Di Bona E. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia N. Engl. J. Med. 2013 369 111 121 10.1056/NEJMoa1300874 23841729

4. Guarnera L. Ottone T. Fabiani E. Divona M. Savi A. Travaglini S. Falconi G. Panetta P. Rapanotti M.C. Voso M.T. Atypical Rearrangements in APL-Like Acute Myeloid Leukemias: Molecular Characterization and Prognosis Front. Oncol. 2022 12 871590 10.3389/fonc.2022.871590 35494081 PMC9039303

5. Fenaux P. Mufti G.J. Hellstrom-Lindberg E. Santini V. Finelli C. Giagounidis A. Schoch R. Gattermann N. Sanz G. List A. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: A randomised, open-label, phase III study Lancet Oncol. 2009 10 223 232 10.1016/S1470-2045(09)70003-8 19230772 PMC4086808

6. DiNardo C.D. Pratz K. Pullarkat V. Jonas B.A. Arellano M. Becker P.S. Frankfurt O. Konopleva M. Wei A.H. Kantarjian H.M. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia Blood 2019 133 7 17 10.1182/blood-2018-08-868752 30361262 PMC6318429

7. Castaigne S. Pautas C. Terré C. Raffoux E. Bordessoule D. Bastie J.-N. Legrand O. Thomas X. Turlure P. Reman O. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): A randomised, open-label, phase 3 study Lancet 2012 379 1508 1516 10.1016/S0140-6736(12)60485-1 22482940

8. Voso M.T. Ottone T. Lavorgna S. Venditti A. Maurillo L. Lo-Coco F. Buccisano F. MRD in AML: The Role of New Techniques Front. Oncol. 2019 9 655 10.3389/fonc.2019.00655 31396481 PMC6664148

9. Tokaz M.C. Baldomero H. Cowan A.J. Saber W. Greinix H. Koh M.B.C. Kröger N. Mohty M. Galeano S. Okamoto S. An Analysis of the Worldwide Utilization of Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia Transplant. Cell Ther. 2023 29 e1 e10 279.e1–279.e10 10.1016/j.jtct.2022.12.013 36572384

10. Kantarjian H.M. Short N.J. Fathi A.T. Marcucci G. Ravandi F. Tallman M. Wang E.S. Wei A.H. Acute Myeloid Leukemia: Historical Perspective and Progress in Research and Therapy over 5 Decades Clin. Lymphoma Myeloma Leuk. 2021 21 580 597 10.1016/j.clml.2021.05.016 34176779 PMC11938811

11. Butturini A. Bortin M.M. Gale R.P. Graft-versus-leukemia following bone marrow transplantation Bone Marrow Transplant. 1987 2 233 242 3332173

12. Guarnera L. Santinelli E. Galossi E. Cristiano A. Fabiani E. Falconi G. Voso M.T. Microenvironment in Acute Myeloid Leukemia: Focus on senescence mechanisms, therapeutic interactions and future directions Exp. Hematol. 2023 10.1016/j.exphem.2023.09.005 37741607

13. Fujisaki J. Wu J. Carlson A.L. Silberstein L. Putheti P. Larocca R. Gao W. Saito T.I. Lo Celso C. Tsuyuzaki H. In vivo imaging of Treg cells providing immune privilege to the haematopoietic stem-cell niche Nature 2011 474 216 219 10.1038/nature10160 21654805 PMC3725645

14. Ros-Soto J. Snowden J.A. Szydlo R. Nicholson E. Madrigal A. Easdale S. Potter M. Ethell M. Anthias C. Outcomes After Donor Lymphocyte Infusion in Patients with Hematological Malignancies: Donor Characteristics Matter Transplant. Cell. Ther. 2022 28 e1 e8 183.e1–183.e8 10.1016/j.jtct.2022.01.022 35104660

15. Sánchez-Abarca L.I. Gutierrez-Cosio S. Santamaría C. Caballero-Velazquez T. Blanco B. Herrero-Sánchez C. García J.L. Carrancio S. Hernández-Campo P. González F.J. Immunomodulatory effect of 5-azacytidine (5-azaC): Potential role in the transplantation setting Blood 2010 115 107 121 10.1182/blood-2009-03-210393 19887673

16. Cooper M.L. Choi J. Karpova D. Vij K. Ritchey J. Schroeder M.A. DiPersio J.F. Azacitidine Mitigates Graft-versus-Host Disease via Differential Effects on the Proliferation of T Effectors and Natural Regulatory T Cells In Vivo J. Immunol. 2017 198 3746 3754 10.4049/jimmunol.1502399 28330901 PMC5541679

17. Grimm J. Simnica D. Jäkel N. Paschold L. Willscher E. Schulze S. Dierks C. Al-Ali H.K. Binder M. Azacitidine-induced reconstitution of the bone marrow T cell repertoire is associated with superior survival in AML patients Blood Cancer J. 2022 12 19 10.1038/s41408-022-00615-7 35091554 PMC8799690

18. Wang L. de Zoeten E.F. Greene M.I. Hancock W.W. Immunomodulatory effects of deacetylase inhibitors: Therapeutic targeting of FOXP3 + regulatory T cells Nat. Rev. Drug Discov. 2009 8 969 981 10.1038/nrd3031 19855427 PMC2884987

19. Licciardi P.V. Karagiannis T.C. Regulation of immune responses by histone deacetylase inhibitors ISRN Hematol. 2012 2012 690901 10.5402/2012/690901 22461998 PMC3313568

20. Xu X. Li X. Zhao Y. Huang H. Immunomodulatory Effects of Histone Deacetylation Inhibitors in Graft-vs.-Host Disease After Allogeneic Stem Cell Transplantation Front. Immunol. 2021 12 641910 10.3389/fimmu.2021.641910 33732262 PMC7959724

21. Mathew N.R. Baumgartner F. Braun L. O’Sullivan D. Thomas S. Waterhouse M. Müller T.A. Hanke K. Taromi S. Apostolova P. Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells Nat. Med. 2018 24 282 291 10.1038/nm.4484 29431743 PMC6029618

22. Massumoto C. Sousa-Canavez J.M. Leite K.R.M. Camara-Lopes L.H. Stabilization of acute myeloid leukemia with a dendritic cell vaccine Hematol. Oncol. Stem Cell Ther. 2008 1 239 240 10.1016/S1658-3876(08)50011-2 20058480

23. Li L. Giannopoulos K. Reinhardt P. Tabarkiewicz J. Schmitt A. Greiner J. Rolinski J. Hus I. Dmoszynska A. Wiesneth M. Immunotherapy for patients with acute myeloid leukemia using autologous dendritic cells generated from leukemic blasts Int. J. Oncol. 2006 28 855 861 10.3892/ijo.28.4.855 16525634

24. Kitawaki T. Kadowaki N. Fukunaga K. Kasai Y. Maekawa T. Ohmori K. Itoh T. Shimizu A. Kuzushima K. Kondo T. Cross-priming of CD8(+) T cells in vivo by dendritic cells pulsed with autologous apoptotic leukemic cells in immunotherapy for elderly patients with acute myeloid leukemia Exp. Hematol. 2011 39 424 433.e2 10.1016/j.exphem.2011.01.001 21216276

25. Dong M. Liang D. Li Y. Kong D. Kang P. Li K. Ping C. Zhang Y. Zhou X. Zhang Y. Autologous dendritic cells combined with cytokine-induced killer cells synergize low-dose chemotherapy in elderly patients with acute myeloid leukaemia J. Int. Med. Res. 2012 40 1265 1274 10.1177/147323001204000405 22971478

26. Rosenblatt J. Stone R.M. Uhl L. Neuberg D. Joyce R. Levine J.D. Arnason J. McMasters M. Luptakova K. Jain S. Individualized vaccination of AML patients in remission is associated with induction of antileukemia immunity and prolonged remissions Sci. Transl. Med. 2016 8 368ra171 10.1126/scitranslmed.aag1298 PMC5800949 27928025

27. Van de Loosdrecht A.A. Cloos J. Wagner E.M. Platzbecker U. Holderried T.A.W. van Elssen J. Giagounidis A. Lehmann S. van Zeeburg H. Rovers J. Treatment with an Allogeneic Leukemia-Derived Dendritic Cell Vaccine in AML Patients Shows MRD Conversion and Improved Survival Blood 2021 138 1274 10.1182/blood-2021-148333

28. Kitawaki T. Kadowaki N. Fukunaga K. Kasai Y. Maekawa T. Ohmori K. Kondo T. Maekawa R. Takahara M. Nieda M. A phase I/IIa clinical trial of immunotherapy for elderly patients with acute myeloid leukaemia using dendritic cells co-pulsed with WT1 peptide and zoledronate Br. J. Haematol. 2011 153 796 799 10.1111/j.1365-2141.2010.08490.x 21477159

29. Shah N.N. Loeb D.M. Khuu H. Stroncek D. Ariyo T. Raffeld M. Delbrook C. Mackall C.L. Wayne A.S. Fry T.J. Induction of Immune Response after Allogeneic Wilms’ Tumor 1 Dendritic Cell Vaccination and Donor Lymphocyte Infusion in Patients with Hematologic Malignancies and Post-Transplantation Relapse Biol. Blood Marrow Transplant. J. Am. Soc. Blood Marrow Transplant. 2016 22 2149 2154 10.1016/j.bbmt.2016.08.028 27634018 PMC7499897

30. Barbullushi K. Rampi N. Serpenti F. Sciumè M. Fabris S. De Roberto P. Fracchiolla N.S. Vaccination Therapy for Acute Myeloid Leukemia: Where Do We Stand? Cancers 2022 14 2994 10.3390/cancers14122994 35740657 PMC9221207

31. Rautenberg C. Germing U. Haas R. Kobbe G. Schroeder T. Relapse of Acute Myeloid Leukemia after Allogeneic Stem Cell Transplantation: Prevention, Detection, and Treatment Int. J. Mol. Sci. 2019 20 228 10.3390/ijms20010228 30626126 PMC6337734

32. Huehls A.M. Coupet T.A. Sentman C.L. Bispecific T-cell engagers for cancer immunotherapy Immunol. Cell Biol. 2015 93 290 296 10.1038/icb.2014.93 25367186 PMC4445461

33. Mocquot P. Mossazadeh Y. Lapierre L. Pineau F. Despas F. The pharmacology of blinatumomab: State of the art on pharmacodynamics, pharmacokinetics, adverse drug reactions and evaluation in clinical trials J. Clin. Pharm. Ther. 2022 47 1337 1351 10.1111/jcpt.13741 35906791 PMC9796714

34. Einsele H. Borghaei H. Orlowski R.Z. Subklewe M. Roboz G.J. Zugmaier G. Kufer P. Iskander K. Kantarjian H.M. The BiTE (bispecific T-cell engager) platform: Development and future potential of a targeted immuno-oncology therapy across tumor types Cancer 2020 126 3192 3201 10.1002/cncr.32909 32401342

35. Ma J. Mo Y. Tang M. Shen J. Qi Y. Zhao W. Huang Y. Xu Y. Qian C. Bispecific Antibodies: From Research to Clinical Application Front. Immunol. 2021 12 626616 10.3389/fimmu.2021.626616 34025638 PMC8131538

36. Sivori S. Pende D. Quatrini L. Pietra G. Della Chiesa M. Vacca P. Tumino N. Moretta F. Mingari M.C. Locatelli F. NK cells and ILCs in tumor immunotherapy Mol. Asp. Med. 2021 80 100870 10.1016/j.mam.2020.100870 32800530

37. Ehninger A. Kramer M. Röllig C. Thiede C. Bornhäuser M. von Bonin M. Wermke M. Feldmann A. Bachmann M. Ehninger G. Distribution and levels of cell surface expression of CD33 and CD123 in acute myeloid leukemia Blood Cancer J. 2014 4 e218 10.1038/bcj.2014.39 24927407 PMC4080210

38. Paterno G. Guarnera L. Palmieri R. Del Prete V. Bonanni F. Buzzatti E. Moretti F. Casciani P. Savi A. Di Cave D. Pneumocystis jirovecii pneumonia in patients with previously untreated acute myeloid leukaemia Mycoses 2022 65 233 238 10.1111/myc.13411 34883533

39. Guarnera L. Trotta G.E. Boldrini V. Cardillo L. Cerroni I. Mezzanotte V. Pasqualone G. Savi A. Borsellino B. Buzzatti E. Fever of Unknown Origin and Multidrug Resistant Organism Colonization in AML Patients Mediterr. J. Hematol. Infect. Dis. 2023 15 e2023013 10.4084/MJHID.2023.013 36660358 PMC9833311

40. Cattaneo C. Di Blasi R. Skert C. Candoni A. Martino B. Di Renzo N. Delia M. Ballanti S. Marchesi F. Mancini V. Bloodstream infections in haematological cancer patients colonized by multidrug-resistant bacteria Ann. Hematol. 2018 97 1717 1726 10.1007/s00277-018-3341-6 29705860

41. McKoy J.M. Angelotta C. Bennett C.L. Tallman M.S. Wadleigh M. Evens A.M. Kuzel T.M. Trifilio S.M. Raisch D.W. Kell J. Gemtuzumab ozogamicin-associated sinusoidal obstructive syndrome (SOS): An overview from the research on adverse drug events and reports (RADAR) project Leuk. Res. 2007 31 599 604 10.1016/j.leukres.2006.07.005 16959316

42. Shimabukuro-Vornhagen A. Gödel P. Subklewe M. Stemmler H.J. Schlößer H.A. Schlaak M. Kochanek M. Böll B. von Bergwelt-Baildon M.S. Cytokine release syndrome J. Immunother. Cancer 2018 6 56 10.1186/s40425-018-0343-9 29907163 PMC6003181

43. Hills R.K. Castaigne S. Appelbaum F.R. Delaunay J. Petersdorf S. Othus M. Estey E.H. Dombret H. Chevret S. Ifrah N. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: A meta-analysis of individual patient data from randomised controlled trials Lancet Oncol. 2014 15 986 996 10.1016/S1470-2045(14)70281-5 25008258 PMC4137593

44. Pemmaraju N. Lane A.A. Sweet K.L. Stein A.S. Vasu S. Blum W. Rizzieri D.A. Wang E.S. Duvic M. Sloan J.M. Tagraxofusp in Blastic Plasmacytoid Dendritic-Cell Neoplasm N. Engl. J. Med. 2019 380 1628 1637 10.1056/NEJMoa1815105 31018069

45. Lane A.A. Stein A.S. Garcia J.S. Garzon J.L. Galinsky I. Luskin M.R. Stone R.M. Winer E.S. Leonard R. Mughal T.I. Safety and Efficacy of Combining Tagraxofusp (SL-401) with Azacitidine or Azacitidine and Venetoclax in a Phase 1b Study for CD123 Positive AML, MDS, or BPDCN Blood 2021 138 2346 10.1182/blood-2021-147486

46. Green S.D. Parkin B. Lai C. Gojo I. Foster M.C. Zeidner J.F. Phase II Study of Tagraxofusp in Newly Diagnosed Secondary Acute Myeloid Leukemia (S-AML) after Previous Exposure to Hypomethylating Agents (TAGALONG Study) Blood 2022 140 11749 11750 10.1182/blood-2022-170738

47. Uy G.L. Rettig M.P. Vey N. Godwin J. Foster M.C. Rizzieri D.A. Arellano M.L. Topp M.S. Huls G. Jongen-Lavrencic M. Phase 1 Cohort Expansion of Flotetuzumab, a CD123×CD3 Bispecific Dart ® Protein in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML) Blood 2018 132 764 10.1182/blood-2018-99-117085

48. Uy G.L. Aldoss I. Foster M.C. Sayre P.H. Wieduwilt M.J. Advani A.S. Godwin J.E. Arellano M.L. Sweet K.L. Emadi A. Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia Blood 2021 137 751 762 10.1182/blood.2020007732 32929488 PMC7885824

49. Ravandi F. Stein A.S. Kantarjian H.M. Walter R.B. Paschka P. Jongen-Lavrencic M. Ossenkoppele G.J. Yang Z. Mehta B. Subklewe M. A Phase 1 First-in-Human Study of AMG 330, an Anti-CD33 Bispecific T-Cell Engager (BiTE ® ) Antibody Construct, in Relapsed/Refractory Acute Myeloid Leukemia (R/R AML) Blood 2018 132 25 10.1182/blood-2018-99-109762

50. Ravandi F. Walter R.B. Subklewe M. Buecklein V. Jongen-Lavrencic M. Paschka P. Ossenkoppele G.J. Kantarjian H.M. Hindoyan A. Agarwal S.K. Updated results from phase I dose-escalation study of AMG 330, a bispecific T-cell engager molecule, in patients with relapsed/refractory acute myeloid leukemia (R/R AML) J. Clin. Oncol. 2020 38 7508 10.1200/JCO.2020.38.15_suppl.7508

51. Subklewe M. Stein A. Walter R.B. Bhatia R. Wei A.H. Ritchie D. Bücklein V. Vachhani P. Dai T. Hindoyan A. Preliminary Results from a Phase 1 First-in-Human Study of AMG 673, a Novel Half-Life Extended (HLE) Anti-CD33/CD3 BiTE ® (Bispecific T-Cell Engager) in Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) Blood 2019 134 833 10.1182/blood-2019-127977

52. Ravandi F. Bashey A. Stock W. Foran J.M. Mawad R. Egan D. Blum W. Yang A. Pastore A. Johnson C. Complete Responses in Relapsed/Refractory Acute Myeloid Leukemia (AML) Patients on a Weekly Dosing Schedule of Vibecotamab (XmAb14045), a CD123 x CD3 T Cell-Engaging Bispecific Antibody; Initial Results of a Phase 1 Study Blood 2020 136 4 5 10.1182/blood-2020-134746

53. Short N.J. Bachireddy P. Huang X. Hwang H. Leng X. Lee J. Nguyen D. Garcia-Manero G. Dinardo C.D. Borthakur G. A phase II study of vibecotamab, a CD3-CD123 bispecific T-cell engaging antibody, for MRD-positive AML and MDS after hypomethylating agent failure J. Clin. Oncol. 2023 41 TPS7076 10.1200/JCO.2023.41.16_suppl.TPS7076

54. Uckun F.M. Lin T.L. Mims A.S. Patel P. Lee C. Shahidzadeh A. Shami P.J. Cull E. Cogle C.R. Watts J. A Clinical Phase 1B Study of the CD3xCD123 Bispecific Antibody APVO436 in Patients with Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome Cancers 2021 13 4113 10.3390/cancers13164113 34439266 PMC8394899

55. Watts J. Maris M. Lin T.L. Patel P. Madanat Y.F. Cogle C.R. Borthakur G. Huebner D. Khaskhely N. Bonham L. Updated Results from a Phase 1 Study of APVO436, a Novel Bispecific Anti-CD123 x Anti-CD3 Adaptir TM Molecule, in Relapsed/Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome Blood 2022 140 6204 6205 10.1182/blood-2022-167468

56. Morsink L.M. Walter R.B. Ossenkoppele G.J. Prognostic and therapeutic role of CLEC12A in acute myeloid leukemia Blood Rev. 2019 34 26 33 10.1016/j.blre.2018.10.003 30401586

57. Mascarenhas J. Cortes J. Huls G. Venditti A. Breems D. De Botton S. Deangelo D. van de Loosdrecht A. Jongen-Lavrencic M. Borthakur G. Update from the Ongoing Phase I Multinational Study of MCLA-117, a Bispecific CLEC12A X CD3 T-Cell Engager, in Patients (Pts) with Acute Myelogenous Leukemia (AML) European Hematology Association Hague, The Netherlands 2020

58. Mehta N.K. Pfluegler M. Meetze K. Li B. Sindel I. Vogt F. Marklin M. Heitmann J.S. Kauer J. Osburg L. A novel IgG-based FLT3xCD3 bispecific antibody for the treatment of AML and B-ALL J. Immunother. Cancer 2022 10 e003882 10.1136/jitc-2021-003882 35288466 PMC8921914

59. Wiernik A. Foley B. Zhang B. Verneris M.R. Warlick E. Gleason M.K. Ross J.A. Luo X. Weisdorf D.J. Walcheck B. Targeting natural killer cells to acute myeloid leukemia in vitro with a CD16 x 33 bispecific killer cell engager and ADAM17 inhibition Clin. Cancer Res. 2013 19 3844 3855 10.1158/1078-0432.CCR-13-0505 23690482 PMC3715574

60. Gleason M.K. Ross J.A. Warlick E.D. Lund T.C. Verneris M.R. Wiernik A. Spellman S. Haagenson M.D. Lenvik A.J. Litzow M.R. CD16xCD33 bispecific killer cell engager (BiKE) activates NK cells against primary MDS and MDSC CD33+ targets Blood 2014 123 3016 3026 10.1182/blood-2013-10-533398 24652987 PMC4014844

61. Reusing S.B. Vallera D.A. Manser A.R. Vatrin T. Bhatia S. Felices M. Miller J.S. Uhrberg M. Babor F. CD16xCD33 Bispecific Killer Cell Engager (BiKE) as potential immunotherapeutic in pediatric patients with AML and biphenotypic ALL Cancer Immunol. Immunother. 2021 70 3701 3708 10.1007/s00262-021-03008-0 34398302 PMC8571204

62. Erica D. Warlick M. Daniel J. Weisdorf M. Daniel A. Vallera P. Wangen R. Dixie Lewis R.N. Knox J. Schroeder M. GTB-3550 TriKE TM for the Treatment of High-Risk Myelodysplastic Syndromes (MDS) and Refractory/Relapsed Acute Myeloid Leukemia (AML) Safely Drives Natural Killer (NK) Cell Proliferation at Initial dose Cohorts Blood 2020 136 7 8

63. Felices M. Warlick E. Juckett M. Weisdorf D. Vallera D. Miller S. Wangen R. Lewis D. Knox J. Schroeder M. GTB-3550 tri-specific killer engager TriKE TM drives NK cells expansion and cytotoxicity in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients J. Immunother. Cancer 2021 9 10.1136/jitc-2021-SITC2021.444

64. Hughes-Parry H.E. Cross R.S. Jenkins M.R. The Evolving Protein Engineering in the Design of Chimeric Antigen Receptor T Cells Int. J. Mol. Sci. 2019 21 204 10.3390/ijms21010204 31892219 PMC6981602

65. Ahmad U. Khan Z. Ualiyeva D. Amissah O.B. Noor Z. Khan A. Zaman N. Khan M. Khan A. Ali B. Chimeric antigen receptor T cell structure, its manufacturing, and related toxicities Chimeric antigen receptor T cell structure, its manufacturing, and related toxicities; A comprehensive review Adv. Cancer Biol.-Metastasis 2022 4 100035 10.1016/j.adcanc.2022.100035

66. Tang H.K.C. Wang B. Tan H.X. Sarwar M.A. Baraka B. Shafiq T. Rao A.R. CAR T-Cell Therapy for Cancer: Latest Updates and Challenges, with a Focus on B-Lymphoid Malignancies and Selected Solid Tumours Cells 2023 12 1586 10.3390/cells12121586 37371056 PMC10296619

67. Wang Q. Wang Y. Lv H. Han Q. Fan H. Guo B. Wang L. Han W. Treatment of CD33-directed chimeric antigen receptor-modified T cells in one patient with relapsed and refractory acute myeloid leukemia Mol. Ther. 2015 23 184 191 10.1038/mt.2014.164 25174587 PMC4426796

68. Wu Z. Zhang H. Wu M. Peng G. He Y. Wan N. Zeng Y. Targeting the NKG2D/NKG2D-L axis in acute myeloid leukemia Biomed. Pharmacother. 2021 137 111299 10.1016/j.biopha.2021.111299 33508619

69. Baumeister S.H. Murad J. Werner L. Daley H. Trebeden-Negre H. Gicobi J.K. Schmucker A. Reder J. Sentman C.L. Gilham D.E. Phase I Trial of Autologous CAR T Cells Targeting NKG2D Ligands in Patients with AML/MDS and Multiple Myeloma Cancer Immunol. Res. 2019 7 100 112 10.1158/2326-6066.CIR-18-0307 30396908 PMC7814996

70. Tambaro F.P. Singh H. Jones E. Rytting M. Mahadeo K.M. Thompson P. Daver N. DiNardo C. Kadia T. Garcia-Manero G. Autologous CD33-CAR-T cells for treatment of relapsed/refractory acute myelogenous leukemia Leukemia 2021 35 3282 3286 10.1038/s41375-021-01232-2 33833386 PMC8550958

71. Hu N. Gao C. Zhang Y. Teng G. Wang Y. Du C. Bai J. Targeted Therapy in CD38 + Acute Myeloid Leukemia Blood 2021 138 4425 10.1182/blood-2021-150193

72. Glisovic-Aplenc T. Diorio C. Chukinas J.A. Veliz K. Shestova O. Shen F. Nunez-Cruz S. Vincent T.L. Miao F. Milone M.C. CD38 as a pan-hematologic target for chimeric antigen receptor T cells Blood Adv. 2023 7 4418 4430 10.1182/bloodadvances.2022007059 37171449 PMC10440474

73. Sallman D.A. Elmariah H. Sweet K. Mishra A. Cox C.A. Chakaith M. Semnani R. Shehzad S. Anderson A. Sabzevari H. Phase 1/1b Safety Study of Prgn-3006 Ultracar-T in Patients with Relapsed or Refractory CD33-Positive Acute Myeloid Leukemia and Higher Risk Myelodysplastic Syndromes Blood 2022 140 10313 10315 10.1182/blood-2022-169142

74. Sallman D.A. DeAngelo D.J. Pemmaraju N. Dinner S. Gill S. Olin R.L. Wang E.S. Konopleva M. Stark E. Korngold A. Ameli-01: A Phase I Trial of UCART123v1.2, an Anti-CD123 Allogeneic CAR-T Cell Product, in Adult Patients with Relapsed or Refractory (R/R) CD123+ Acute Myeloid Leukemia (AML) Blood 2022 140 2371 2373 10.1182/blood-2022-169928

75. Naik S. Madden R.M. Lipsitt A. Lockey T. Bran J. Rubnitz J.E. Klco J. Shulkin B. Patil S.L. Schell S. Safety and Anti-Leukemic Activity of CD123-CAR T Cells in Pediatric Patients with AML: Preliminary Results from a Phase 1 Trial Blood 2022 140 4584 4585 10.1182/blood-2022-170201

76. Zhang H. Gan W.-T. Hao W.-G. Wang P.-F. Li Z.-Y. Chang L.-J. Successful Anti-CLL1 CAR T-Cell Therapy in Secondary Acute Myeloid Leukemia Front. Oncol. 2020 10 685 10.3389/fonc.2020.00685 32528876 PMC7266936

77. Jin X. Zhang M. Sun R. Lyu H. Xiao X. Zhang X. Li F. Xie D. Xiong X. Wang J. First-in-human phase I study of CLL-1 CAR-T cells in adults with relapsed/refractory acute myeloid leukemia J. Hematol. Oncol. 2022 15 88 10.1186/s13045-022-01308-1 35799191 PMC9264641

78. Zhang H. Bu C. Peng Z. Luo M. Li C. The efficacy and safety of anti-CLL1 based CAR-T cells in children with relapsed or refractory acute myeloid leukemia: A multicenter interim analysis J. Clin. Oncol. 2021 39 10000 10.1200/JCO.2021.39.15_suppl.10000 36151140

79. Zhang H. Bu C. Peng Z. Li G. Zhou Z. Ding W. Zheng Y. He Y. Hu Z. Pei K. Characteristics of anti-CLL1 based CAR-T therapy for children with relapsed or refractory acute myeloid leukemia: The multi-center efficacy and safety interim analysis Leukemia 2022 36 2596 2604 10.1038/s41375-022-01703-0 36151140

80. Pei K. Xu H. Wang P. Gan W. Hu Z. Su X. Zhang H. He Y. Anti-CLL1-based CAR T-cells with 4-1-BB or CD28/CD27 stimulatory domains in treating childhood refractory/relapsed acute myeloid leukemia Cancer Med. 2023 12 9655 9661 10.1002/cam4.5916 37031462 PMC10166968

81. Huang R. Wen Q. Wang X. Yan H. Ma Y. Mai-Hong W. Han X. Gao L. Gao L. Zhang C. Off-the-Shelf CD33 CAR-NK Cell Therapy for Relapse/Refractory AML: First-in-Human, Phase I Trial Blood 2022 140 7450 7451 10.1182/blood-2022-170712

82. Lu Y. Liu Y. Wen S. Kuang N. Zhang X. Li J. Wang F. Naturally selected CD7 CAR-T therapy without genetic editing demonstrates significant antitumour efficacy against relapsed and refractory acute myeloid leukaemia (R/R-AML) J. Transl. Med. 2022 20 600 10.1186/s12967-022-03797-7 36517851 PMC9753314

83. Francis J. Dharmadhikari A.V. Sait S.N.J. Deeb G. Wallace P.K. Thompson J.E. Wang E.S. Wetzler M. CD19 expression in acute leukemia is not restricted to the cytogenetically aberrant populations Leuk. Lymphoma 2013 54 1517 1520 10.3109/10428194.2012.754096 23193950 PMC6668030

84. Tang L. Huang H. Tang Y. Li Q. Wang J. Li D. Zhong Z. Zou P. You Y. Cao Y. CD44v6 chimeric antigen receptor T cell specificity towards AML with FLT3 or DNMT3A mutations Clin. Transl. Med. 2022 12 e1043 10.1002/ctm2.1043 36163632 PMC9513046

85. Riether C. Pabst T. Höpner S. Bacher U. Hinterbrandner M. Banz Y. Müller R. Manz M.G. Gharib W.H. Francisco D. Targeting CD70 with cusatuzumab eliminates acute myeloid leukemia stem cells in patients treated with hypomethylating agents Nat. Med. 2020 26 1459 1467 10.1038/s41591-020-0910-8 32601337

86. Niswander L.M. Graff Z.T. Chien C.D. Chukinas J.A. Meadows C.A. Leach L.C. Loftus J.P. Kohler M.E. Tasian S.K. Fry T.J. Potent preclinical activity of FLT3-directed chimeric antigen receptor T-cell immunotherapy against FLT3- mutant acute myeloid leukemia and KMT2A-rearranged acute lymphoblastic leukemia Haematologica 2023 108 457 471 10.3324/haematol.2022.281456 35950535 PMC9890025

87. Shao R. Li Z. Xin H. Jiang S. Zhu Y. Liu J. Huang R. Xu K. Shi X. Biomarkers as targets for CAR-T/NK cell therapy in AML Biomark. Res. 2023 11 65 10.1186/s40364-023-00501-9 37330575 PMC10276424

88. Lichtman E.I. Du H. Shou P. Song F. Suzuki K. Ahn S. Li G. Ferrone S. Su L. Savoldo B. Preclinical Evaluation of B7-H3-specific Chimeric Antigen Receptor T Cells for the Treatment of Acute Myeloid Leukemia Clin. Cancer Res. 2021 27 3141 3153 10.1158/1078-0432.CCR-20-2540 33531429 PMC8248479

89. Hargadon K.M. Johnson C.E. Williams C.J. Immune checkpoint blockade therapy for cancer: An overview of FDA-approved immune checkpoint inhibitors Int. Immunopharmacol. 2018 62 29 39 10.1016/j.intimp.2018.06.001 29990692

90. Kuzume A. Chi S. Yamauchi N. Minami Y. Immune-Checkpoint Blockade Therapy in Lymphoma Int. J. Mol. Sci. 2020 21 5456 10.3390/ijms21155456 32751706 PMC7432396

91. Jiang Z. Sun H. Yu J. Tian W. Song Y. Targeting CD47 for cancer immunotherapy J. Hematol. Oncol. 2021 14 180 10.1186/s13045-021-01197-w 34717705 PMC8557524

92. Komori S. Saito Y. Nishimura T. Respatika D. Endoh H. Yoshida H. Sugihara R. Iida-Norita R. Afroj T. Takai T. CD47 promotes peripheral T cell survival by preventing dendritic cell-mediated T cell necroptosis Proc. Natl. Acad. Sci. USA 2023 120 e2304943120 10.1073/pnas.2304943120 37549290 PMC10440595

93. Majeti R. Chao M.P. Alizadeh A.A. Pang W.W. Jaiswal S. Gibbs K.D.J. van Rooijen N. Weissman I.L. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells Cell 2009 138 286 299 10.1016/j.cell.2009.05.045 19632179 PMC2726837

94. Yan X. Lai B. Zhou X. Yang S. Ge Q. Zhou M. Shi C. Xu Z. Ouyang G. The Differential Expression of CD47 may be Related to the Pathogenesis From Myelodysplastic Syndromes to Acute Myeloid Leukemia Front. Oncol. 2022 12 872999 10.3389/fonc.2022.872999 35433462 PMC9008711

95. Jaiswal S. Jamieson C.H.M. Pang W.W. Park C.Y. Chao M.P. Majeti R. Traver D. van Rooijen N. Weissman I.L. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis Cell 2009 138 271 285 10.1016/j.cell.2009.05.046 19632178 PMC2775564

96. Tseng D. Volkmer J.-P. Willingham S.B. Contreras-Trujillo H. Fathman J.W. Fernhoff N.B. Seita J. Inlay M.A. Weiskopf K. Miyanishi M. Anti-CD47 antibody-mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response Proc. Natl. Acad. Sci. USA 2013 110 11103 11108 10.1073/pnas.1305569110 23690610 PMC3703977

97. Zeidan A.M. DeAngelo D.J. Palmer J.M. Seet C.S. Tallman M.S. Wei X. Li Y.F. Hock N. Burgess M.R. Hege K. A Phase I Study of CC-90002, a Monoclonal Antibody Targeting CD47, in Patients with Relapsed and/or Refractory (R/R) Acute Myeloid Leukemia (AML) and High-Risk Myelodysplastic Syndromes (MDS): Final Results Blood 2019 134 1320 10.1182/blood-2019-125363

98. Sallman D.A. Asch A.S. Al Malki M.M. Lee D.J. Donnellan W.B. Marcucci G. Kambhampati S. Daver N.G. Garcia-Manero G. Komrokji R.S. The First-in-Class Anti-CD47 Antibody Magrolimab (5F9) in Combination with Azacitidine Is Effective in MDS and AML Patients: Ongoing Phase 1b Results Blood 2019 134 569 10.1182/blood-2019-126271

99. Sallman D. Asch A. Kambhampati S. Al Malki M. Zeidner J. Donnellan W. Lee D. Vyas P. Jeyakumar D. Mannis G. AML-196: The First-in-Class Anti-CD47 Antibody Magrolimab in Combination with Azacitidine Is Well Tolerated and Effective in AML Patients: Phase 1b Results Clin. Lymphoma Myeloma Leuk. 2021 21 S290 10.1016/S2152-2650(21)01694-3

100. Gilead To Discontinue Phase 3 ENHANCE Study of Magrolimab Plus Azacitidine in Higher-Risk MDS Gilead Sciences Foster City, CA, USA 2023

101. Qi J. Li J. Jiang B. Jiang B. Liu H. Cao X. Zhang M. Meng Y. Xiaoyu M.A. Jia Y. A Phase I/IIa Study of Lemzoparlimab, a Monoclonal Antibody Targeting CD47, in Patients with Relapsed and/or Refractory Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS): Initial Phase I Results Blood 2020 136 30 31 10.1182/blood-2020-134391

102. Garcia-Manero G. Przespolewski A. Abaza Y. Byrne M. Fong A.P. Jin F. Forgie A.J. Tsiatis A.C. Guan S. Erba H.P. Evorpacept (ALX148), a CD47-Blocking Myeloid Checkpoint Inhibitor, in Combination with Azacitidine and Venetoclax in Patients with Acute Myeloid Leukemia (ASPEN-05): Results from Phase 1a Dose Escalation Part Blood 2022 140 9046 9047 10.1182/blood-2022-157606

103. Sharpe A.H. Pauken K.E. The diverse functions of the PD1 inhibitory pathway Nat. Rev. Immunol. 2018 18 153 167 10.1038/nri.2017.108 28990585

104. Keir M.E. Butte M.J. Freeman G.J. Sharpe A.H. PD-1 and its ligands in tolerance and immunity Annu. Rev. Immunol. 2008 26 677 704 10.1146/annurev.immunol.26.021607.090331 18173375 PMC10637733

105. Riley J.L. PD-1 signaling in primary T cells Immunol. Rev. 2009 229 114 125 10.1111/j.1600-065X.2009.00767.x 19426218 PMC3424066

106. Han Y. Liu D. Li L. PD-1/PD-L1 pathway: Current researches in cancer Am. J. Cancer Res. 2020 10 727 742 32266087 PMC7136921

107. Brodská B. Otevřelová P. Šálek C. Fuchs O. Gašová Z. Kuželová K. High PD-L1 Expression Predicts for Worse Outcome of Leukemia Patients with Concomitant NPM1 and FLT3 Mutations Int. J. Mol. Sci. 2019 20 2823 10.3390/ijms20112823 31185600 PMC6600137

108. Yang X. Ma L. Zhang X. Huang L. Wei J. Targeting PD-1/PD-L1 pathway in myelodysplastic syndromes and acute myeloid leukemia Exp. Hematol. Oncol. 2022 11 11 10.1186/s40164-022-00263-4 35236415 PMC8889667

109. Williams P. Basu S. Garcia-Manero G. Hourigan C.S. Oetjen K.A. Cortes J.E. Ravandi F. Jabbour E.J. Al-Hamal Z. Konopleva M. The distribution of T-cell subsets and the expression of immune checkpoint receptors and ligands in patients with newly diagnosed and relapsed acute myeloid leukemia Cancer 2019 125 1470 1481 10.1002/cncr.31896 30500073 PMC6467779

110. Tang L. Wu J. Li C.-G. Jiang H.-W. Xu M. Du M. Yin Z. Mei H. Hu Y. Characterization of Immune Dysfunction and Identification of Prognostic Immune-Related Risk Factors in Acute Myeloid Leukemia Clin. Cancer Res. 2020 26 1763 1772 10.1158/1078-0432.CCR-19-3003 31911547

111. Damiani D. Tiribelli M. Checkpoint Inhibitors in Acute Myeloid Leukemia Biomedicines 2023 11 1724 10.3390/biomedicines11061724 37371818 PMC10295997

112. Daver N.G. Basu S. Garcia-Manero G. Cortes J.E. Ravandi F. Jabbour E. Hendrickson S. Brandt M. Pierce S. Gordon T. Phase IB/II study of nivolumab with azacytidine (AZA) in patients (pts) with relapsed AML J. Clin. Oncol. 2017 35 7026 10.1200/JCO.2017.35.15_suppl.7026

113. Ravandi F. Daver N. Garcia-Manero G. Benton C.B. Thompson P.A. Borthakur G. Kadia T. Boddu P.C. Alvarado Y. Jabbour E.J. Phase 2 Study of Combination of Cytarabine, Idarubicin, and Nivolumab for Initial Therapy of Patients with Newly Diagnosed Acute Myeloid Leukemia Blood 2017 130 815 10.1182/blood.V130.Suppl_1.815.815

114. Ravandi F. Assi R. Daver N. Benton C.B. Kadia T. Thompson P.A. Borthakur G. Alvarado Y. Jabbour E.J. Konopleva M. Idarubicin, cytarabine, and nivolumab in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome: A single-arm, phase 2 study Lancet Haematol. 2019 6 e480 e488 10.1016/S2352-3026(19)30114-0 31400961 PMC6778960

115. Kadia T.M. Cortes J.E. Ghorab A. Ravandi F. Jabbour E. Daver N.G. Alvarado Y. Ohanian M. Konopleva M. Kantarjian H.M. Nivolumab (Nivo) maintenance (maint) in high-risk (HR) acute myeloid leukemia (AML) patients J. Clin. Oncol. 2018 36 7014 10.1200/JCO.2018.36.15_suppl.7014

116. Reville P.K. Kantarjian H.M. Ravandi F. Jabbour E. DiNardo C.D. Daver N. Pemmaraju N. Ohanian M. Alvarado Y. Xiao L. Nivolumab maintenance in high-risk acute myeloid leukemia patients: A single-arm, open-label, phase II study Blood Cancer J. 2021 11 60 10.1038/s41408-021-00453-z 33731681 PMC7969746

117. Liu H. Sharon E. Karrison T.G. Zha Y. Fulton N. Streicher H. Sweet K. Yaghmour G. Liu J.J. Jonas B.A. Randomized Phase II Study to Assess the Role of Nivolumab As Single Agent to Eliminate Minimal Residual Disease and Maintain Remission in Acute Myelogenous Leukemia (AML) Patients after Chemotherapy (NCI9706 protocol; REMAIN Trial) Blood 2022 140 1716 1719 10.1182/blood-2022-157326

118. Gojo I. Stuart R.K. Webster J. Blackford A. Varela J.C. Morrow J. DeZern A.E. Foster M.C. Levis M.J. Coombs C.C. Multi-Center Phase 2 Study of Pembroluzimab (Pembro) and Azacitidine (AZA) in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML) and in Newly Diagnosed (≥65 Years) AML Patients Blood 2019 134 832 10.1182/blood-2019-127345

119. Goswami M. Gui G. Dillon L.W. Lindblad K.E. Thompson J. Valdez J. Kim D.-Y. Ghannam J.Y. Oetjen K.A. Destefano C.B. Pembrolizumab and decitabine for refractory or relapsed acute myeloid leukemia J. Immunother. Cancer 2022 10 e003392 10.1136/jitc-2021-003392 35017151 PMC8753450

120. Zeidner J.F. Vincent B.G. Ivanova A. Moore D. McKinnon K.P. Wilkinson A.D. Mukhopadhyay R. Mazziotta F. Knaus H.A. Foster M.C. Phase II Trial of Pembrolizumab after High-Dose Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia Blood Cancer Discov. 2021 2 616 629 10.1158/2643-3230.BCD-21-0070 34778801 PMC8580622

121. Tschernia N.P. Kumar V. Moore D.T. Vincent B.G. Coombs C.C. Van Deventer H. Foster M.C. DeZern A.E. Luznik L. Riches M.L. Safety and Efficacy of Pembrolizumab Prior to Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia Transplant. Cell. Ther. 2021 27 e1 e5 1021.e1–1021.e5 10.1016/j.jtct.2021.08.022 34474164

122. Solomon S.R. Solh M.M. Morris L.E. Holland H.K. Bachier-Rodriguez L. Zhang X. Guzowski C. Jackson K.C. Brown S. Bashey A. Phase 2 Study of PD-1 blockade following autologous transplantation for patients with AML ineligible for allogeneic transplant Blood Adv. 2023 7 5215 5224 10.1182/bloodadvances.2023010477 37379271 PMC10500475

123. Zeidan A.M. Boss I. Beach C.L. Copeland W.B. Thompson E. Fox B.A. Hasle V.E. Hellmann A. Taussig D.C. Tormo M. A randomized phase 2 trial of azacitidine with or without durvalumab as first-line therapy for older patients with AML Blood Adv. 2022 6 2219 2229 10.1182/bloodadvances.2021006138 34933333 PMC9006260

124. Zhu C. Anderson A.C. Schubart A. Xiong H. Imitola J. Khoury S.J. Zheng X.X. Strom T.B. Kuchroo V.K. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity Nat. Immunol. 2005 6 1245 1252 10.1038/ni1271 16286920

125. Ndhlovu L.C. Lopez-Vergès S. Barbour J.D. Jones R.B. Jha A.R. Long B.R. Schoeffler E.C. Fujita T. Nixon D.F. Lanier L.L. Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity Blood 2012 119 3734 3743 10.1182/blood-2011-11-392951 22383801 PMC3335380

126. Sakuishi K. Ngiow S.F. Sullivan J.M. Teng M.W.L. Kuchroo V.K. Smyth M.J. Anderson A.C. TIM3(+)FOXP3(+) regulatory T cells are tissue-specific promoters of T-cell dysfunction in cancer Oncoimmunology 2013 2 e23849 10.4161/onci.23849 23734331 PMC3654601

127. Tao J. Li L. Fu R. Wang H. Jiang H. Yue L. Zhang W. Liu H. Ruan E. Qu W. Elevated TIM3+ hematopoietic stem cells in untreated myelodysplastic syndrome displayed aberrant differentiation, overproliferation and decreased apoptosis Leuk. Res. 2014 38 714 721 10.1016/j.leukres.2014.03.018 24746294

128. Mohamed M.M.I. Aref S. Agdar M.A. Mabed M. El-Sokkary A.M.A. Leukemic Stem Cell (CD34(+)/CD38(-)/TIM3(+)) Frequency in Patients with Acute Myeloid Leukemia: Clinical Implications Clin. Lymphoma. Myeloma Leuk. 2021 21 508 513 10.1016/j.clml.2021.03.009 33931379

129. Tan J. Yu Z. Huang J. Chen Y. Huang S. Yao D. Xu L. Lu Y. Chen S. Li Y. Increased PD-1+Tim-3+ exhausted T cells in bone marrow may influence the clinical outcome of patients with AML Biomark. Res. 2020 8 6 10.1186/s40364-020-0185-8 32082573 PMC7020501

130. Kong Y. Zhang J. Claxton D.F. Ehmann W.C. Rybka W.B. Zhu L. Zeng H. Schell T.D. Zheng H. PD-1(hi)TIM-3(+) T cells associate with and predict leukemia relapse in AML patients post allogeneic stem cell transplantation Blood Cancer J. 2015 5 e330 10.1038/bcj.2015.58 26230954 PMC4526784

131. Li C. Chen X. Yu X. Zhu Y. Ma C. Xia R. Ma J. Gu C. Ye L. Wu D. Tim-3 is highly expressed in T cells in acute myeloid leukemia and associated with clinicopathological prognostic stratification Int. J. Clin. Exp. Pathol. 2014 7 6880 6888 25400771 PMC4230106

132. Zahran A.M. Mohammed Saleh M.F. Sayed M.M. Rayan A. Ali A.M. Hetta H.F. Up-regulation of regulatory T cells, CD200 and TIM3 expression in cytogenetically normal acute myeloid leukemia Cancer Biomark. 2018 22 587 595 10.3233/CBM-181368 29843224 PMC13078467

133. Darwish N.H.E. Sudha T. Godugu K. Elbaz O. Abdelghaffar H.A. Hassan E.E.A. Mousa S.A. Acute myeloid leukemia stem cell markers in prognosis and targeted therapy: Potential impact of BMI-1, TIM-3 and CLL-1 Oncotarget 2016 7 57811 57820 10.18632/oncotarget.11063 27506934 PMC5295391

134. Kikushige Y. Shima T. Takayanagi S. Urata S. Miyamoto T. Iwasaki H. Takenaka K. Teshima T. Tanaka T. Inagaki Y. TIM-3 is a promising target to selectively kill acute myeloid leukemia stem cells Cell Stem Cell 2010 7 708 717 10.1016/j.stem.2010.11.014 21112565

135. Brunner A. Borate U. Esteve J. Porkka K. Knapper S. Vey N. Scholl S. Wermke M. Janssen J. Traer E. AML-190: Anti-TIM-3 Antibody MBG453 in Combination with Hypomethylating Agents (HMAs) in Patients with High-Risk Myelodysplastic Syndrome (HR-MDS) and Acute Myeloid Leukemia: A Phase 1 Study Clin. Lymphoma Myeloma Leuk. 2020 20 S188 S189 10.1016/S2152-2650(20)30728-X

136. Brunner A.M. Esteve J. Porkka K. Knapper S. Traer E. Scholl S. Garcia-Manero G. Vey N. Wermke M. Janssen J. Efficacy and Safety of Sabatolimab (MBG453) in Combination with Hypomethylating Agents (HMAs) in Patients (Pts) with Very High/High-Risk Myelodysplastic Syndrome (vHR/HR-MDS) and Acute Myeloid Leukemia (AML): Final Analysis from a Phase Ib Study Blood 2021 138 244 10.1182/blood-2021-146039

137. Nolte M.A. van Olffen R.W. van Gisbergen K.P.J.M. van Lier R.A.W. Timing and tuning of CD27-CD70 interactions: The impact of signal strength in setting the balance between adaptive responses and immunopathology Immunol. Rev. 2009 229 216 231 10.1111/j.1600-065X.2009.00774.x 19426224

138. Riether C. Schürch C.M. Bührer E.D. Hinterbrandner M. Huguenin A.-L. Hoepner S. Zlobec I. Pabst T. Radpour R. Ochsenbein A.F. CD70/CD27 signaling promotes blast stemness and is a viable therapeutic target in acute myeloid leukemia J. Exp. Med. 2017 214 359 380 10.1084/jem.20152008 28031480 PMC5294846

139. Pabst T. Vey N. Adès L. Bacher U. Bargetzi M. Fung S. Gaidano G. Gandini D. Hultberg A. Johnson A. Results from a phase I/II trial of cusatuzumab combined with azacitidine in patients with newly diagnosed acute myeloid leukemia who are ineligible for intensive chemotherapy Haematologica 2023 108 1793 1802 10.3324/haematol.2022.281563 36779592 PMC10316251

140. Roboz G.J. Pabst T. Aribi A. Brandwein J.M. Döhner H. Fiedler W. Gandini D. Geddes M. Hou J.-Z. Howes A.J. Safety and Efficacy of Cusatuzumab in Combination with Venetoclax and Azacitidine (CVA) in Patients with Previously Untreated Acute Myeloid Leukemia (AML) Who Are Not Eligible for Intensive Chemotherapy; An Open-Label, Multicenter, Phase 1b Study Blood 2021 138 369 10.1182/blood-2021-150371

141. Rowshanravan B. Halliday N. Sansom D.M. CTLA-4: A moving target in immunotherapy Blood 2018 131 58 67 10.1182/blood-2017-06-741033 29118008 PMC6317697

142. Chen C. Liang C. Wang S. Chio C.L. Zhang Y. Zeng C. Chen S. Wang C. Li Y. Expression patterns of immune checkpoints in acute myeloid leukemia J. Hematol. Oncol. 2020 13 28 10.1186/s13045-020-00853-x 32245463 PMC7118887

143. Zhong R.K. Loken M. Lane T.A. Ball E.D. CTLA-4 blockade by a human MAb enhances the capacity of AML-derived DC to induce T-cell responses against AML cells in an autologous culture system Cytotherapy 2006 8 3 12 10.1080/14653240500499507 16627340

144. Bashey A. Medina B. Corringham S. Pasek M. Carrier E. Vrooman L. Lowy I. Solomon S.R. Morris L.E. Holland H.K. CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation Blood 2009 113 1581 1588 10.1182/blood-2008-07-168468 18974373 PMC2644086

145. Garcia J.S. Flamand Y. Penter L. Keng M. Tomlinson B.K. Mendez L.M. Koller P. Cullen N. Arihara Y. Pfaff K. Ipilimumab plus decitabine for patients with MDS or AML in posttransplant or transplant-naïve settings Blood 2023 141 1884 1888 10.1182/blood.2022017686 36332187 PMC10122101

146. Kotwica-Mojzych K. Jodłowska-Jędrych B. Mojzych M. CD200:CD200R Interactions and Their Importance in Immunoregulation Int. J. Mol. Sci. 2021 22 1602 10.3390/ijms22041602 33562512 PMC7915401

147. Coles S.J. Wang E.C.Y. Man S. Hills R.K. Burnett A.K. Tonks A. Darley R.L. CD200 expression suppresses natural killer cell function and directly inhibits patient anti-tumor response in acute myeloid leukemia Leukemia 2011 25 792 799 10.1038/leu.2011.1 21274000 PMC3093357

148. Memarian A. Nourizadeh M. Masoumi F. Tabrizi M. Emami A.H. Alimoghaddam K. Hadjati J. Mirahmadian M. Jeddi-Tehrani M. Upregulation of CD200 is associated with Foxp3+ regulatory T cell expansion and disease progression in acute myeloid leukemia Tumour Biol. 2013 34 531 542 10.1007/s13277-012-0578-x 23179394

149. Tiribelli M. Geromin A. Cavallin M. Di Giusto S. Simeone E. Fanin R. Damiani D. ABCG2 and CD200 define patients at high risk of relapse in ELN favorable subgroup of AML Eur. J. Haematol. 2017 99 269 274 10.1111/ejh.12915 28618016

150. Tiribelli M. Raspadori D. Geromin A. Cavallin M. Sirianni S. Simeone E. Bocchia M. Fanin R. Damiani D. High CD200 expression is associated with poor prognosis in cytogenetically normal acute myeloid leukemia, even in FlT3-ITD-/NPM1+ patients Leuk. Res. 2017 58 31 38 10.1016/j.leukres.2017.04.001 28407515

151. Aref S. Abousamra N. El-Helaly E. Mabed M. Clinical Significance of CD200 and CD56 Expression in Patients with Acute Myeloid Leukemia Asian Pac. J. Cancer Prev. 2020 21 743 748 10.31557/APJCP.2020.21.3.743 32212802 PMC7437307

152. Herbrich S. Baran N. Cai T. Weng C. Aitken M.J.L. Post S.M. Henderson J. Shi C. Richard-Carpentier G. Sauvageau G. Overexpression of CD200 is a Stem Cell-Specific Mechanism of Immune Evasion in AML J. Immunother. Cancer 2021 9 e002968 10.1136/jitc-2021-002968 34326171 PMC8323398

153. Rastogi N. Baker S. Man S. Uger R.A. Wong M. Coles S.J. Hodges M. Gilkes A.F. Knapper S. Darley R.L. Use of an anti-CD200-blocking antibody improves immune responses to AML in vitro and in vivo Br. J. Haematol. 2021 193 155 159 10.1111/bjh.17125 32996123 PMC9851282

154. Maruhashi T. Sugiura D. Okazaki I.-M. Okazaki T. LAG-3: From molecular functions to clinical applications J. Immunother. Cancer 2020 8 e001014 10.1136/jitc-2020-001014 32929051 PMC7488795

155. Radwan S.M. Elleboudy N.S. Nabih N.A. Kamal A.M. The immune checkpoints Cytotoxic T lymphocyte antigen-4 and Lymphocyte activation gene-3 expression is up-regulated in acute myeloid leukemia HLA 2020 96 3 12 10.1111/tan.13872 32189430

156. Chen Y. Tan J. Huang S. Huang X. Huang J. Chen J. Yu Z. Lu Y. Weng J. Du X. Higher frequency of the CTLA-4(+) LAG-3(+) T-cell subset in patients with newly diagnosed acute myeloid leukemia Asia. Pac. J. Clin. Oncol. 2020 16 e12 e18 10.1111/ajco.13236 31612643

157. Tettamanti S. Pievani A. Biondi A. Dotti G. Serafini M. Catch me if you can: How AML and its niche escape immunotherapy Leukemia 2022 36 13 22 10.1038/s41375-021-01350-x 34302116 PMC8727297