LAUSR

Simple Summary Despite increasing knowledge of the biological mechanisms leading to neoplastic transformation, the identification of various molecular targets for innovative drugs, refinements in supportive care, and the wider use of allogeneic transplants, the prognosis of acute myeloid leukemia (AML) remains dismal. In the last years, the role of the bone marrow microenvironment and of the immune system in favoring leukemic cell persistence has emerged both as a cause of treatment failure but also as a potential setting for novel therapies. The aim of the present paper is to review the biological evidence and clinical trials of immune-based treatments for AML. Abstract It is now well known that the bone marrow (BM) cell niche contributes to leukemogenesis, but emerging data support the role of the complex crosstalk between AML cells and the BM microenvironment to induce a permissive immune setting that protects leukemic stem cells (LSCs) from therapy-induced death, thus favoring disease persistence and eventual relapse. The identification of potential immune targets on AML cells and the modulation of the BM environment could lead to enhanced anti-leukemic effects of drugs, immune system reactivation, and the restoration of AML surveillance. Potential targets and effectors of this immune-based therapy could be monoclonal antibodies directed against LSC antigens such as CD33, CD123, and CLL-1 (either as direct targets or via several bispecific T-cell engagers), immune checkpoint inhibitors acting on different co-inhibitory axes (alone or in combination with conventional AML drugs), and novel cellular therapies such as chimeric antigen receptor (CAR) T-cells designed against AML-specific antigens. Though dozens of clinical trials, mostly in phases I and II, are ongoing worldwide, results have still been negatively affected by difficulties in the identification of the optimal targets on LSCs.