Abstract
The concept of leukemic stem cells (LSC) has been developed with the idea to explain the clonal hierarchies and architectures in leukemia, and the more or less curative anti-neoplastic effects of various targeted drugs. It is now widely accepted that curative therapies must have the potential to eliminate or completely suppress LSC, as only these cells can restore and propagate the malignancy for unlimited time periods. Since LSC represent a minor cell fraction in the leukemic clone, little is known about their properties and target expression profiles. Over the past few years, several cell-specific immunotherapy concepts have been developed, including new generations of cell-targeting antibodies, antibody–toxin conjugates, bispecific antibodies, and CAR-T cell-based strategies. Whereas such concepts have been translated and may improve outcomes of therapy in certain lymphoid neoplasms and a few other malignancies, only little is known about immunological targets that are clinically relevant and can be employed to establish such therapies in myeloid neoplasms. In the current article, we provide an overview of the immunologically relevant molecular targets expressed on LSC in patients with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). In addition, we discuss the current status of antibody-based therapies in these malignancies, their mode of action, and successful examples from the field.
Highlights
Acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) are stem cell-derived, life-threatening, hematopoietic neoplasms that are characterized by an uncontrolled expansion of myeloid progenitor cells exhibiting a more or less severe maturation defect
In patients with multi-resistant disease, hematopoietic stem cell transplantation (HSCT) is usually recommended, but the procedure can only be performed in a limited number of ‘young’ and fit patients, and carries an inherent mortality risk
Certain drugs, such as the hypomethylating agents can increase the expression of PD-L1 on leukemic cells, including AML blasts and AML leukemic stem cells (LSC) [119]
Summary
Acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) are stem cell-derived, life-threatening, hematopoietic neoplasms that are characterized by an uncontrolled expansion of myeloid progenitor cells exhibiting a more or less severe maturation defect. Depending on the molecular background and the phase of the disease, at least some LSC may be detected within a CD34+/CD38+ subset of leukemic cells, or sometimes even in a CD34-negative cell population [23,24,25] Based on their disease-initiating and disease-propagating capacity, LSC are regarded as a major, clinically relevant therapeutic cell target, and numerous studies have been conducted with the goal of identifying new molecular targets in these cells [17,18,19,20,21,22,26,27,28,29]. We review the cell surface antigens that are expressed preferentially or even on LSC in AML and/or CML, and represent potential targets for immunotherapies. We discuss future developments in the field, and how LSC-targeting immunotherapies can be translated into clinical application
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