Abstract
In the past few years, our improved knowledge of acute myeloid leukemia (AML) pathogenesis has led to the accelerated discovery of new drugs and the development of innovative therapeutic approaches. The role of the immune system in AML development, growth and recurrence has gained increasing interest. A better understanding of immunological escape and systemic tolerance induced by AML blasts has been achieved. The extraordinary successes of immune therapies that harness the power of T cells in solid tumors and certain hematological malignancies have provided new stimuli in this area of research. Accordingly, major efforts have been made to develop immune therapies for the treatment of AML patients. The persistence of leukemia stem cells, representing the most relevant cause of relapse, even after allogeneic stem cell transplant (allo-SCT), remains a major hurdle in the path to cure for AML patients. Several clinical trials with immune-based therapies are currently ongoing in the frontline, relapsed/refractory, post-allo-SCT and minimal residual disease/maintenance setting, with the aim to improve survival of AML patients. This review summarizes the available data with immune-based therapeutic modalities such as monoclonal antibodies (naked and conjugated), T cell engagers, adoptive T-cell therapy, adoptive-NK therapy, checkpoint blockade via PD-1/PD-L1, CTLA4, TIM3 and macrophage checkpoint blockade via the CD47/SIRPa axis, and leukemia vaccines. Combining clinical results with biological immunological findings, possibly coupled with the discovery of biomarkers predictive for response, will hopefully allow us to determine the best approaches to immunotherapy in AML.
Highlights
Acute myeloid leukemia (AML) is a clonal disease characterized by the rapid proliferation of immature myeloid cells in the bone marrow with impaired differentiation [1]
Beyond the identification of an optimal target antigen and of the best strategy to prevent prolonged and not acceptable myelosuppression, a very active area of preclinical and biological research points toward the identification of the immunosuppressive effects induced by acute myeloid leukemia (AML) microenvironment in dampening the therapeutic response of adoptively transferred chimeric antigen receptor (CAR)-T cells, to what observed in other settings of adoptive immunotherapy
Moving from the hypothesis that generating more homogeneous and well-defined allogeneic Natural killer (NK)-cell products may be associated with better clinical results, the authors had previously developed a culture system where CD34+ human stem/progenitor cells (HSPC) isolated from allogeneic umbilical cord blood (UCB) were expanded and differentiated into NK cells in the presence of IL15 and IL2, resulting in a clinically relevant dose of highly purified NK cells [132, 133]
Summary
Acute myeloid leukemia (AML) is a clonal disease characterized by the rapid proliferation of immature myeloid cells in the bone marrow with impaired differentiation [1]. Despite major progresses in AML therapy and high rates of complete remission (CR) after intensive chemotherapy, many patients will eventually relapse and die from the disease. The identification of disease-specific molecular aberrations has triggered the development of targeted therapies (e.g.: FLT3 inhibitors, IDH1/2 inhibitors), to improve the clinical outcome of AML patients [2, 3]. We have better understood the mechanisms underlying the ability of AML cells to induce immunological escape and systemic tolerance [9, 10]. Such tolerogenic pathways, which create an immunosuppressive microenvironment, have been suggested to both critically hamper anti-leukemia immune responses and to negatively impact the anti-leukemia efficacy of conventional and experimental therapies. 1/PD-L1, CTLA4, TIM3 and macrophage checkpoint blockade via the CD47/SIRPa axis
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