Dendritic Cell-Based Immunotherapy for Myeloid Leukemias

Abstract

Acute and chronic myeloid leukemia (AML, CML) are hematologic malignancies arising from oncogene-transformed hematopoietic stem/progenitor cells known as leukemia stem cells (LSCs). LSCs are selectively resistant to various forms of therapy including irradiation or cytotoxic drugs. The introduction of tyrosine kinase inhibitors has dramatically improved disease outcome in patients with CML. For AML, however, prognosis is still quite dismal. Standard treatments have been established more than 20 years ago with only limited advances ever since. Durable remission is achieved in less than 30% of patients. Minimal residual disease (MRD), reflected by the persistence of LSCs below the detection limit by conventional methods, causes a high rate of disease relapses. Therefore, the ultimate goal in the treatment of myeloid leukemia must be the eradication of LSCs. Active immunotherapy, aiming at the generation of leukemia-specific cytotoxic T cells (CTLs), may represent a powerful approach to target LSCs in the MRD situation. To fully activate CTLs, leukemia antigens have to be successfully captured, processed, and presented by mature dendritic cells (DCs). Myeloid progenitors are a prominent source of DCs under homeostatic conditions, and it is now well established that LSCs and leukemic blasts can give rise to “malignant” DCs. These leukemia-derived DCs can express leukemia antigens and may either induce anti-leukemic T cell responses or favor tolerance to the leukemia, depending on co-stimulatory or -inhibitory molecules and cytokines. This review will concentrate on the role of DCs in myeloid leukemia immunotherapy with a special focus on their generation, application, and function and how they could be improved in order to generate highly effective and specific anti-leukemic CTL responses. In addition, we discuss how DC-based immunotherapy may be successfully integrated into current treatment strategies to promote remission and potentially cure myeloid leukemias.

Immunotherapy based on dendritic cells pulsed with CTPFoxM1 fusion protein protects against the development of hepatocellular carcinoma

“…Dendritic cells (DCs) are the most powerful professional antigen-presenting cells (APCs) that can induce antitumor immunity by initiating an antigen-specific cytotoxic T lymphocyte (CTL) response, and application of dendritic cells (DCs) loaded with tumor antigens as anti-tumor vaccines has shown a great potential in therapy and prophylaxis of cancer [3]. DC-based vaccines have been successfully used for the treatment of several cancers including malignant melanoma, HCC, multiple myeloma, acute myeloid leukemia, etc [4–6]. …”

Generation of populations of antigen-specific cytotoxic T cells using DCs transfected with DNA construct encoding HER2/neu tumor antigen epitopes

“…It is currently possible to isolate CTLs specific for certain antigenic determinants from heterogeneous peripheral blood mononuclear cell (PBMC) populations, thus making it possible to target specific cell-mediated immune responses against tumor cells carrying these antigens [7, 10, 11]. A number of procedures employing MHC molecules have been developed to isolate populations of antigen-specific T cells.…”

Effective Dendritic Cell-based Immunotherapeutic Vaccines for Acute Myeloid Leukemia (AML)

“…These newly-adopted "leukemia stem cells (LSCs)" share the most relevant features of the normal hematopoetic stem cells (HSCs) such as the selfrenewal potential and dormant status. It would be difficult to find various pools of leukemic stem cells within the individual patients which differ both phenotypically and molecularly [7,8]. Despite intensive consolidation chemotherapy in AML patients, the relapses occur in 50% of the patients due to the presence of minimal residual disease (MRD) [3,9,10].…”