Dendritic Cell-Based Immunotherapy of Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia (AML) is a type of blood cancer characterized by the uncontrolled clonal proliferation of myeloid hematopoietic progenitor cells in the bone marrow. The outcome of AML is poor, with five-year overall survival rates of less than 10% for the predominant group of patients older than 65 years. One of the main reasons for this poor outcome is that the majority of AML patients will relapse, even after they have attained complete remission by chemotherapy. Chemotherapy, supplemented with allogeneic hematopoietic stem cell transplantation in patients at high risk of relapse, is still the cornerstone of current AML treatment. Both therapies are, however, associated with significant morbidity and mortality. These observations illustrate the need for more effective and less toxic treatment options, especially in elderly AML and have fostered the development of novel immune-based strategies to treat AML. One of these strategies involves the use of a special type of immune cells, the dendritic cells (DCs). As central orchestrators of the immune system, DCs are key to the induction of anti-leukemia immunity. In this review, we provide an update of the clinical experience that has been obtained so far with this form of immunotherapy in patients with AML.

Keywords: acute myeloid leukemia; dendritic cells; immunotherapy.

Figure 1

Dendritic cells are key to the induction of adaptive and innate anti-leukemia immunity. Dendritic cells (DCs) can stimulate both adaptive and innate immune responses against acute myeloid leukemia (AML) cells [12]. There exist two types of adaptive immune responses: humoral or B-cell-mediated (not shown in this figure), and cellular or T-cell-mediated immune responses. The initiation of the latter type of immune response involves the presentation of AML-related antigens (Ag) by DCs via major histocompatibility complex (MHC) class I and II molecules to CD8⁺ cytotoxic T-lymphocytes (CTLs) and CD4⁺ helper T cells, respectively. If appropriately stimulated, naive CD4⁺ T cells (T_H0) can be polarized into T helper type 1 (T_H1) cells, which in turn support the generation of antigen-specific CTLs (+). These CTLs—via their specific T-cell receptor (TCR)—are capable of recognizing AML cells that display the particular antigen(s) to which the CTLs are directed [12]. CTLs possess different tools in their armamentarium to kill AML cells, such as death receptor ligands (e.g., Fas ligand (FasL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)) and cytolytic proteins released from intracytoplasmic granules (e.g., granzyme B and perforin) [16]. The innate arm of the immune system is unequivocally important for mounting effective anti-leukemia immunity [20]. Innate effector cells, predominantly natural killer (NK) cells, are able to eradicate AML cells in a non-antigen-specific, non-MHC-restricted manner. NK cells can utilize the same cytolytic tools as CTLs [16]. In addition to their direct cytotoxic activity, NK cells also play an immunoregulatory role by secreting cytokines such as interferon (IFN)-γ. Through this so-called “helper” function, NK cells can support the generation of T_H1 and CTL responses [21,22]. Several DC-derived cytokines are known to be involved in DC-mediated NK-cell activation, including interleukin (IL)-12 and IL-15 [23]. The latter is usually not secreted by the DCs, but “trans-presented” on the DC surface via IL-15 receptor-α [24,25].