Dendritic Cell-Based Immunotherapy in Myeloid Leukaemia: Translating Fundamental Mechanisms into Clinical Applications

Abstract

Immunotherapy for leukaemia patients, aiming at the generation of anti-leukaemic T cell responses, could provide a new therapeutic approach to eliminate minimal residual disease (MRD) cells in acute myeloid leukaemia (AML). Leukaemic blasts harbour several ways to escape the immune system including deficient MHC class II expression, low levels of co-stimulatory molecules and suppressive cytokines. Therapeutic vaccination with dendritic cells (DC) is now recognized as an important investigational therapy. Due to their unique antigen presenting capacity, immunosuppressive features of the leukaemic blasts can be circumvented. DC can be successfully cultured from leukaemic blasts in 60-70% of patients and show functional potential in vivo. Alternatively, monocyte derived DC obtained at time of complete remission loaded with leukaemia-specific antigens can be used as vaccine. Several sources of leukaemia-associated antigen and different methods of loading antigen onto DC have been used in an attempt to optimize antitumour responses including apoptotic cells, necrotic cell lysates and tumour-associated pep-tides. Currently, the AML-derived cell line MUTZ-3, an immortalized equivalent of CD34(+) DC precursor cells, is under investigation for vaccination purposes. For effective DC vaccination the intrinsic tolerant state of the patient must be overcome. Therefore, the development of efficient and safe adjuvants in antigen specific immunotherapeutic programs should be encouraged.

Dendritic Cell-Based Immunotherapy for Myeloid Leukemias

“…Because of their excellent ability to activate T cells, DCs are considered as one of the most promising tools for tumor-antigen delivery in active cancer immunotherapy and they are ideal candidates to supply foreign tumor-antigen in the form of a DC-based vaccine or for the generation of tumor-antigen-specific CTLs in vitro (185). Clinical studies have used various precursor cells in order to manufacture sufficient ex vivo tumor-antigen loaded DCs for immunotherapeutic purposes (186).…”

“…Originally, mDCs have been cultured together with AML cell lysates or immunogenic apoptotic/necrotic AML cells to ensure LAA loading [Figure 3 (185)]. As an additional approach, AML blast-mDC cell-fusion hybrids have been generated in vitro [Figure 3 (196)].…”

“…In addition, these approaches circumvent the need for previous identification of the LAAs. On the other hand, co-culturing or fusion approaches might negatively impact the antigen uptake and processing and/or the maturation of DCs because of immunosuppressive factors stored in or produced by AML cells, such as TGF-β (185). Nevertheless, Herr et al have shown that tumor cell lysate-loaded DCs were superior to DCs loaded with eluted peptides in inducing an anti-tumoral immune response against an EBV + B lymphoblastic cell line (197).…”

“…(B) CD14 + monocytes from patients or healthy donors are differentiated into monocyte-derived DCs (mDCs). These mDCs are cultured together with (C) AML cell lysates or immunogenic apoptotic/necrotic AML cells (185) or (D) are electroporated with mRNA from AML cells (191) to ensure leukemia antigen loading. (E) As an additional in vitro approach, AML blast-mDC cell-fusion hybrids are artificially generated (196).…”

Immunotherapy and Therapeutic antibodies

“…The AML-derived cell line MUTZ-3, an immortalized equivalent of CD34(+) Dendritic cells precursor cells, is under investigation for vaccination purposes. [46] Clinical relevant responses to Dendritic cells based immunotherapy are likely to only occur in non-end-stage patients [47]. Induction of antigenspecific T-cell tolerance in the thymus and its maintenance in the periphery is crucial for the prevention of autoimmunity [48].…”