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The New Challenge of Curing AML: Analysis of Mechanisms of...
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The New Challenge of Curing AML: Analysis of Mechanisms of Resistance of Target Drugs and Future Perspectives

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: 20 March 2025 | Viewed by 2331

Special Issue Editor

Dr. Debora Capelli

E-Mail Website
Guest Editor
Departement of Haematology, Azienda Ospedaliera Universitaria Ospedali Riuniti di Ancona, Via Conca 71, 60126 Ancona, Italy
Interests: acute myeloid leukemia; hemopoietic stem cell transplant; target therapy; mechanisms of resistance; minimal residual disease

Special Issue Information

Dear Colleagues,

The advent of new target drugs for use in treatment has improved the prognosis of AML without changing the indications for allogeneic transplantation. Only 30% of patients with adverse- and intermediate-risk AML survive in the long term. On this basis, understanding the mechanisms behind resistance is critical to treating AML. Identifying molecular mutations that emerge after treatment with target drugs can help to select new targets and their inhibitors. LSCs still represent the major unmet medical need in resistant and refractory disease. Analysis of the metabolism of LSCs and their resistance to target drugs also represents a potential attempt to identify targets for the eradication of minimal residual disease. Inhibitors of FLT3, IDH1-2, and BCL-2, as well as immunotherapies such as monoclonal antibodies, CART, and anti-PD1/PD-L1, should be analyzed in terms of escape mechanisms and future prospects.

We are pleased to invite authors in this field to write reviews discussing the mechanisms of resistance of new target drugs in AML. We will also accept original research articles analyzing the in vivo and in vitro resistance mechanisms of target drugs or escape mechanisms of LSCs and stroma, as well as articles reviewing currently available immunotherapies and immunological escape mechanisms. Discussions of target drugs, pharmacological characteristics and drug interactions with dosage adjustments are also welcome. Finally, there is a need to discuss the prospects of new drugs, currently under investigation, that can be used to overcome resistance.

I look forward to receiving your contributions.

Dr. Debora Capelli
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • AML
  • FLT3 inhibitors
  • BCL2 inhibitor
  • MCL1
  • IDH1-2 inhibitors
  • venetoclax
  • CAR-T
  • anti-CD123 monoclonal antibodies
  • anti-CD33 monoclonal antibodies
  • anti-PD-1 and -PD-L1

Published Papers (2 papers)

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Review

29 pages, 1556 KiB  
Review
The Immunotherapy of Acute Myeloid Leukemia: A Clinical Point of View
by Federico Mosna
Cancers 2024, 16(13), 2359; https://doi.org/10.3390/cancers16132359 - 27 Jun 2024
Viewed by 1144
Abstract
The potential of the immune system to eradicate leukemic cells has been consistently demonstrated by the Graft vs. Leukemia effect occurring after allo-HSCT and in the context of donor leukocyte infusions. Various immunotherapeutic approaches, ranging from the use of antibodies, antibody–drug conjugates, bispecific [...] Read more.
The potential of the immune system to eradicate leukemic cells has been consistently demonstrated by the Graft vs. Leukemia effect occurring after allo-HSCT and in the context of donor leukocyte infusions. Various immunotherapeutic approaches, ranging from the use of antibodies, antibody–drug conjugates, bispecific T-cell engagers, chimeric antigen receptor (CAR) T-cells, and therapeutic infusions of NK cells, are thus currently being tested with promising, yet conflicting, results. This review will concentrate on various types of immunotherapies in preclinical and clinical development, from the point of view of a clinical hematologist. The most promising therapies for clinical translation are the use of bispecific T-cell engagers and CAR-T cells aimed at lineage-restricted antigens, where overall responses (ORR) ranging from 20 to 40% can be achieved in a small series of heavily pretreated patients affected by refractory or relapsing leukemia. Toxicity consists mainly in the occurrence of cytokine-release syndrome, which is mostly manageable with step-up dosing, the early use of cytokine-blocking agents and corticosteroids, and myelosuppression. Various cytokine-enhanced natural killer products are also being tested, mainly as allogeneic off-the-shelf therapies, with a good tolerability profile and promising results (ORR: 20–37.5% in small trials). The in vivo activation of T lymphocytes and NK cells via the inhibition of their immune checkpoints also yielded interesting, yet limited, results (ORR: 33–59%) but with an increased risk of severe Graft vs. Host disease in transplanted patients. Therefore, there are still several hurdles to overcome before the widespread clinical use of these novel compounds. Full article
(This article belongs to the Special Issue The New Challenge of Curing AML: Analysis of Mechanisms of Resistance of Target Drugs and Future Perspectives)
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17 pages, 2213 KiB  
Review
FLT3-Mutated Leukemic Stem Cells: Mechanisms of Resistance and New Therapeutic Targets
by Debora Capelli
Cancers 2024, 16(10), 1819; https://doi.org/10.3390/cancers16101819 - 10 May 2024
Viewed by 958
Abstract
Despite the availability of target drugs in the first and second line, only 30% of FLT3mut AMLs are cured. Among the multiple mechanisms of resistance, those of FLT3mut LSC are the most difficult to eradicate because of their metabolic and genomic characteristics. Reactivation [...] Read more.
Despite the availability of target drugs in the first and second line, only 30% of FLT3mut AMLs are cured. Among the multiple mechanisms of resistance, those of FLT3mut LSC are the most difficult to eradicate because of their metabolic and genomic characteristics. Reactivation of glycogen synthesis, inhibition of the RAS/MAPK pathway, and degradation of FLT3 may be potential aids to fight the resistance of LSC to FLT3i. LSC is also characterized by the expression of a CD34+/CD25+/CD123+/CD99+ immunophenotype. The receptor and ligand of FLT3, the natural killer group 2 member D ligand (NKGD2L), and CD123 are some of the targets of chimeric antigen receptor T cells (CAR-T), bispecific T-cell engager molecules (BiTEs), CAR-NK and nanoparticles recently designed and reported here. The combination of these new therapeutic options, hopefully in a minimal residual disease (MRD)-driven approach, could provide the future answer to the challenge of treating FLT3mut AML. Full article
(This article belongs to the Special Issue The New Challenge of Curing AML: Analysis of Mechanisms of Resistance of Target Drugs and Future Perspectives)
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