Harnessing Immune Response in Acute Myeloid Leukemia

Abstract

Despite the results achieved with the evolution of conventional chemotherapy and the inclusion of targeted therapies in the treatment of acute myeloid leukemia (AML), survival is still not satisfying, in particular in the setting of relapsed/refractory (R/R) disease or elderly/unfit patients. Among the most innovative therapeutic options, cellular therapy has shown great results in different hematological malignancies such as acute lymphoblastic leukemia and lymphomas, with several products already approved for clinical use. However, despite the great interest in also expanding the application of these new treatments to R/R AML, no product has been approved yet for clinical application. Furthermore, cellular therapy could indeed represent a powerful tool and an appealing alternative to allogeneic hematopoietic stem cell transplantation for ineligible patients. In this review, we aim to provide an overview of the most recent clinical research exploring the effectiveness of cellular therapy in AML, moving from consolidated approaches such as post- transplant donor's lymphocytes infusion, to modern adoptive immunotherapies such as alloreactive NK cell infusions, engineered T and NK cells (CAR-T, CAR-NK) and novel platforms of T and NK cells engaging (i.e., BiTEs, DARTs and ANKET^TM).

Keywords: AML; CAR-T; NK cells; immunotherapy.

Figure 1

Mechanisms of T and NK-cell mediated killing. (A) Regulation of T and NK killing in physiological conditions. Cytotoxic T Lymphocytes express antigen-specific T cell receptors (TCRs) to recognize cognate peptides (antigens) bound to human leukocyte antigen (HLA) molecules on target cells. The binding of peptide/HLA-I complexes by TCR initiates T cell activation that converges in cytolytic activity. NK cell mediated-killing is regulated by complex interactions between inhibitory and activating receptors binding various ligands, including HLA-I, that prevents the killing of healthy autologous cells expressing appropriate levels of all self-HLA alleles and low/negative levels of ligands for activating receptors (left panel). The downregulation of HLA-I molecules on neoplastic cells induces NK-mediated killing by a “missing-self” recognition mechanism. NK cell-activating receptors are co-responsible for NK activation interacting with ligands overexpressed on neoplastic cells. Furthermore, NK cells kill neoplastic cells through the recognition of non-self HLA-I molecules (“KIR/KIR-ligand mismatch”), a mechanism of immunosurveillance active in the context of allogeneic-hematopoietic stem cell transplantation and in strategies of adoptive immunotherapies by alloreactive NK cells infusion (right panel). (B) CTLs and NK engineered with chimeric antigen receptors (CAR). The chimeric antigen receptor is made by a monoclonal antibody capable of binding to a specific identified target antigen, coupled with the activation of the intracellular proliferation signal domain. When the chimeric receptor binds to the antigen expressed in malignant cells, it stimulates the activation signal, leading to CAR-T cell activation and to the killing effects. (C) Novel platforms for T and NK cells engaging (see text for details).

Figure 2

A comprehensive overview of cell-based immunotherapy strategies for acute myeloid leukemia treatment.