Renewing the immunological approach to AML treatment: from novel pathways to innovative therapies

Although in the last years major strides have been made in the understanding of the molecular basis of acute myeloid leukemia (AML), these relevant biological advances have had weak, if any, impact on the development of effective therapies for AML patients. Indeed, if the identification of molecular mutations within AML cell population has resulted in better risk-stratification, the vast majority of patients are treated with the same chemotherapy regimens and allogeneic stem cell transplant still represents the only curative option for intermediate and high-risk AML. In this context, increasing interest has gained the role that different cell components of the immune system may have for AML development and growth. In particular, a better knowledge of the mechanisms underlying the ability of AML cells of inducing immunological escape and systemic tolerance has been achieved. Based on these findings, the immunological way to the treatment of AML patients is becoming attractive and promising. The current review offers an overview of the tolerogenic mechanisms and pathways by focusing on those with potential clinical impact for the management of AML patients. Particularly, by moving from the biological significance of the underlying immunological pathways, we will discuss the clinical potential and application of a variety of different strategies, such as immunological checkpoint regulators, inhibitors of small molecules catabolism, i.e. indoleamine 2,3-dyoxigenase, anti-leukemia vaccines, adoptive immunotherapy with chimeric antigen receptor T cells and natural killer cells, monoclonal antibodies, including BiTEs engagers.