The Immunotherapy of Acute Myeloid Leukemia: A Clinical Point of View

Simple Summary Despite significant advancements, acute myeloid leukemia (AML) still remains characterized by a dismal prognosis in too many patients, and oftentimes, a cure can be achieved only after allogeneic hematopoietic stem cell transplantation (allo-HSCT), a procedure hampered by severe treatment-related complications. Despite this, new technologies have made it possible to harness the activity of the immune system against AML and use it as a new form of therapy, and intense research in the field has been made in recent years. This review aims to summarize the main concepts and strategies under study, considered from the point of view of the practicing hematologist, with special interest in the underlying biological principles and on treatment safety and efficacy. It will hopefully provide physicians, as well as the curious enthusiasts, with an updated, critically assessed description of immunotherapy as part of a more precise oncology approach to the treatment of AML.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 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.