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Acute myeloid leukemia (AML) is the most common acute leukemia in adults. The standard of care in medically and physically fit patients is intensive induction therapy. The majority of these intensively treated patients achieve a complete remission. However, a high number of these patients will experience relapse. In patients older than 60 years, the results are even worse. Therefore, new therapeutic approaches are desperately needed. One promising approach in high-risk leukemia to prevent relapse is the induction of the immune system simultaneously or after reduction of the initial tumor burden. Different immunotherapeutic approaches such as allogenic stem cell transplantation or donor lymphocyte infusions are already standard therapies, but other options for AML treatment are in the pipeline. Moreover, the therapeutic landscape in AML is rapidly changing, and in the last years, a number of immunogenic targets structures eligible for specific therapy, risk assessment or evaluation of disease course were determined. For example, leukemia-associated antigens (LAA) showed to be critical as biomarkers of disease state and survival, as well as markers of minimal residual disease (MRD). Yet many mechanisms and properties are still insufficiently understood, which also represents a great potential for this form of therapy. Therefore, targeted therapy as immunotherapy could turn into an efficient tool to clear residual disease, improve the outcome of AML patients and reduce the relapse risk. In this review, established but also emerging immunotherapeutic approaches for AML patients will be discussed., publishedVersion

BMI-1 and EZH2 are polycomb group (PcG) proteins that maintain self-renewal of stem cells, and are overexpressed in leukemia. To investigate the potential of PcG proteins as leukemia-associated antigens, and as targets for graft-versus-leukemia (GVL) effects, we studied cells obtained from 86 patients with chronic myeloid leukemia (CML) and 25 human leukocyte antigen (HLA)-A*0201(+) sibling donors collected before allogeneic stem cell transplantation (SCT). Although BMI-1 overexpression in CD34(+) cells of CML patients treated with pharmacotherapy is associated with poor prognosis, we found, conversely, that in CML patients treated with SCT, a higher expression of BMI-1, and correspondingly a lower expression of its target for repression, CDKN2A, is associated with improved leukemia-free survival. Cytotoxic T-lymphocyte (CTL) responses to the BMI-1 peptide were detected in 5 of 25 (20%) donors, and in 8 of 19 (42%) HLA-A*0201(+) CML patients. BMI-1 generated more total and high-avidity immune responses, and was more immunogenic than EZH2. PcG-specific CTLs had a memory phenotype, were readily expanded in short-term cultures and were detected after SCT in recipients of PcG-specific CTL-positive donors. A higher BMI-1 expression in CML CD34(+) progenitors was associated with native BMI-1 immune responses. These immune responses to PcG proteins may target leukemia stem cells and have relevance for disease control by GVL.