Recent Advances in Immune-Based Therapies for Acute Myeloid Leukemia

Blood Cancer Discovery, Journal Year: 2024, Volume and Issue: 5(4), P. 234 - 248

Published: June 21, 2024

Despite advancements, acute myeloid leukemia (AML) remains unconquered by current therapies. Evidence of immune evasion during AML progression, such as HLA loss and T-cell exhaustion, suggests that antileukemic responses contribute to disease control could be harnessed immunotherapy. In this review, we discuss a spectrum immunotherapy targets, encompassing cancer cell-intrinsic surface antigens well targeting in the leukemic milieu, how they can tailored for personalized approaches. These targets are overviewed across major modalities applied AML: checkpoint inhibitors, antibody-drug conjugates, therapeutic vaccines, bispecific/trispecific antibodies, chimeric antigen receptor (CAR)-T CAR-NK cells. Significance: Immune therapies treatment show evolving promise. Ongoing research aims customize approaches varied patient profiles clinical scenarios. This review covers surveillance mechanisms, therapy options like CAR-T/NK cells, resistance mechanisms microenvironment considerations.

Language: Английский

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CD56neg CD16+ cells represent a distinct mature NK cell subset with altered phenotype and are associated with adverse clinical outcome upon expansion in AML

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 10, 2025

Acute myeloid leukemia (AML) is a rare haematological cancer with poor 5-years overall survival (OS) and high relapse rate. Leukemic cells are sensitive to Natural Killer (NK) cell mediated killing. However, NK highly impaired in AML, which promote AML immune escape from surveillance. We made the first report of CD56neg CD16+ expansion AML. This unconventional subset has been reported expand some chronic viral infections. Although it unclear whether mechanism common across diseases, seems more relevant than ever further investigate this subset, representing potential therapeutic target. used PBMCs patients HV perform mass cytometry, spectral flow bulk RNA-seq vitro assays order better characterize that confirmed represent unique coexpressing Eomes T-bet. could recover CD56 expression where they displayed unaltered functions. previously demonstrated at diagnosis was associated adverse clinical outcome Here, we validated our findings validation cohort N=38 patients. had decreased (HR[CI95]=5.5[1.2-24.5], p=0.0251) relapse-free (HR[CI95]=13.1[1.9-87.5], p=0.0079) compared without after 36 months follow-up. unveiled were mature circulating functional capacities. Upon expansion, showed altered proteomic phenotype, increased frequency terminally expressing TIGIT along Siglec-7+ cells. Taken together, results suggest harness cytotoxic restore anti-tumor response improve patients' prognosis. To conclude, target for future NK-cell-based immunotherapies

Language: Английский

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Maintenance Therapy in AML: What Is the Future Potential?

American Journal of Hematology, Journal Year: 2025, Volume and Issue: 100(S2), P. 38 - 49

Published: Feb. 17, 2025

ABSTRACT Over the last decade, there have been significant advancements in treatment for patients with acute myeloid leukemia (AML) including addition of novel, targeted agents to intensive or nonintensive chemotherapy regimens. However, despite this, majority will still ultimately relapse and long‐term survival remains poor. While use maintenance therapy has emerged as a potential strategy maintain more durable remissions improve overall survival, optimal these therapies not yet clearly defined. In this review, we provide comprehensive overview evolution strategies AML present commentary on future therapy, pressing, unmet needs field.

Language: Английский

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Assessing the role of bronchoscopy in the management of patients with acute leukemia—a transversal study and proposal of evaluation

Hematology Transfusion and Cell Therapy, Journal Year: 2025, Volume and Issue: 47(1), P. 103741 - 103741

Published: Jan. 1, 2025

Bronchoscopy is frequently performed in the management of patients with acute leukemia due to their high susceptibility infections. In this setting, it context lung infiltrates on imaging and persistent fever immunocompromised subjects. This study aimed evaluate utility bronchoscopy leukemia, its diagnostic yield, impact decisions. a single-center cross-sectional that included diagnosed any phenotype who received intensive chemotherapy. Consecutive underwent as part work-up for associated infections were selected, while had undergone bone marrow transplant excluded. investigated patient characteristics changes clinical management. Seventy-nine at various stages treatment analyzed. The most frequent type was myeloid accounting 68.3 % cases. induction phase prevalent (29.1 %) stage. Bacterial cultures positive 17 out 74 evaluated, Pseudomonas aeruginosa being identified microorganism. A change medical observed 18.2 cases, only six experienced secondary complications. first Brazilian managing infectious complications leukemia. less than anticipated, largely low yield identifying causative agents. Nevertheless, remains safe procedure can be useful specific situations.

Language: Английский

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Natural killer cells in combination with the inhibition of telomerase induced apoptosis in Acute Myeloid Leukemia cells

Biochemistry and Biophysics Reports, Journal Year: 2025, Volume and Issue: 42, P. 102027 - 102027

Published: April 26, 2025

Language: Английский

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STAT3 in acute myeloid leukemia facilitates natural killer cell-mediated surveillance

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: July 5, 2024

Acute myeloid leukemia (AML) is a heterogenous disease characterized by the clonal expansion of progenitor cells. Despite recent advancements in treatment AML, relapse still remains significant challenge, necessitating development innovative therapies to eliminate minimal residual disease. One promising approach address these unmet clinical needs natural killer (NK) cell immunotherapy. To implement such treatments effectively, it vital comprehend how AML cells escape NK-cell surveillance. Signal transducer and activator transcription 3 (STAT3), component Janus kinase (JAK)-STAT signaling pathway, well-known for its role driving immune evasion various cancer types. Nevertheless, specific function STAT3 from NK has not been deeply investigated. In this study, we unravel novel sensitizing We demonstrate that STAT3-deficient lines are inefficiently eliminated Mechanistically, lacking fail form an synapse as efficiently their wild-type counterparts due significantly reduced surface expression intercellular adhesion molecule 1 (ICAM-1). The impaired killing can be rescued ICAM-1 overexpression proving central observed phenotype. Importantly, analysis our patient cohort revealed positive correlation between ICAM1 suggesting predominant regulation line, high correlates with better survival patients underscoring translational relevance findings. Taken together, data unveil preventing escaping surveillance highlight STAT3/ICAM-1 axis potential biomarker AML.

Language: Английский

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Proteasome inhibition enhances the anti-leukemic efficacy of chimeric antigen receptor (CAR) expressing NK cells against acute myeloid leukemia

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: Sept. 16, 2024

Relapsed and refractory acute myeloid leukemia (AML) carries a dismal prognosis. CAR T cells have shown limited efficacy in AML, partially due to dysfunctional autologous the extended time for generation of patient specific cells. Allogeneic NK cell therapy is promising alternative, but strategies enhance persistence may be necessary. Proteasome inhibitors (PI) induce changes surface proteome which render malignant more vulnerable mediated cytotoxicity. Here, we investigated potential benefit combining PIs with CAR-expressing allogeneic against AML.

Language: Английский

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Single-cell transcriptomics reveals heterogeneity and prognostic markers of myeloid precursor cells in acute myeloid leukemia

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Dec. 16, 2024

Acute myeloid leukemia (AML) is a hematologic tumor with poor prognosis and significant clinical heterogeneity. By integrating transcriptomic data, single-cell RNA sequencing data independently collected this study aims to identify key genes in AML establish prognostic assessment model improve the accuracy of prediction.

Language: Английский

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Cytokine‐Induced Memory‐Like NK Cells: Emerging strategy for AML immunotherapy

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 168, P. 115718 - 115718

Published: Oct. 17, 2023

Acute myeloid leukemia (AML) is a heterogeneous disease developed from the malignant expansion of precursor cells in bone marrow and peripheral blood. The implementation intensive chemotherapy hematopoietic stem cell transplantation (HSCT) has improved outcomes associated with AML, but relapse, along suboptimal outcomes, still common scenario. In past few years, exploring new therapeutic strategies to optimize treatment occurred rapidly. this regard, natural killer (NK) cell-based immunotherapy attracted clinical interest due its critical role immunosurveillance their capabilities target AML blasts. NK are cytotoxic innate lymphoid that mediate anti-viral anti-tumor responses by producing pro-inflammatory cytokines directly inducing cytotoxicity. Although well known as short-lived immune non-specific have limited applications, discovery cytokine-induced memory-like (CIML) could overcome these challenges. pre-activated cytokine combination IL-12/15/18 achieved long-term life span adaptive immunity characteristics, termed CIML-NK cells. Previous studies documented using cancer safe results promising outcomes. This review highlights current application, challenges, opportunities therapy AML.

Language: Английский

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The SUMOylation inhibitor TAK-981 (Subasumstat) triggers IFN-I-dependent activation of Natural Killer cells against Acute Myeloid Leukemias

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 21, 2024

Abstract Natural Killer (NK) cells play a pivotal role in mounting an anti-cancer immune response. Patients with diminished NK number and activity face less favorable prognosis. Promising therapeutic strategies include the adoptive transfer of or reactivation patients’ own cells. TAK-981, first-in-class inhibitor SUMOylation undergoing phase I/II clinical trials for cancer, is emerging as immunomodulatory drug. Here, we demonstrate that TAK-981 activates from healthy donors patients Acute Myeloid Leukemia (AML), cancer very poor heightens their degranulation capacity, secretion inflammatory cytokines (IFN-γ, TNF-α, FasL), cytotoxicity against AML In vivo , also enhances anti-leukemic ex-vivo expanded human At molecular level, first induces IFNB1 gene cells, leading to type I Interferon (IFN-I), which binds receptor IFNAR. This Interferon-Stimulated Genes (ISG) vitro . Finally, stimulates IFN-I by monocytes, contributes activation trans Altogether, targeting could be promising strategy reactivate enhance efficiency cells-based therapies. Figure

Language: Английский

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