Dendritic Cells Derived In Vitro From Acute Myelogenous Leukemia Cells Stimulate Autologous, Antileukemic T-Cell Responses

Abstract

We have previously reported that leukemic dendritic cells (DC) can be generated ex vivo from myelomonocytic precursors in chronic myelogenous leukemia. In this study we report the generation of DC from acute myelogenous leukemia (AML) cells and their potent ability to stimulate leukemia-specific cytolytic activity in autologous lymphocytes. DC were generated in vitro using granulocyte-macrophage colony-stimulating factor +interleukin-4 in combination with either tumor necrosis factor- or CD40 ligand (CD40L). Cells from 19 AML patients with a variety of chromosomal abnormalities were studied for their ability to generate DC. In all but 1 case, cells with the morphology, phenotypic characteristics, and T-cell stimulatory properties of DC could be generated. These cells expressed high levels of major histocompatibility complex class I and class II antigens as well as the costimulatory molecules B7-2 and ICAM-1. In three cases these cells were determined to be of leukemic origin by fluorescence in situ hybridization for chromosomal abnormalities or Western blotting for the inv(16) fusion gene product. Autologous lymphocytes cocultured with AML-derived DC (DC-AL) were able to lyse autologous leukemia targets, whereas little cytotoxicity was noted against autologous, normal cells obtained from the patients during remission. We conclude that leukemia derived DC may be useful for immunotherapy of many AML patients.

Cytokine‐Driven Differentiation of Blasts from Patients with Acute Myelogenous and Lymphoblastic Leukemia into Dendritic Cells

“…Recent reports have shown that the same might become possible for patients with AML [8, 9, 15, 16]. Although the success of DC cultures varied from patient to patient, leukemic DC could be generated in two‐thirds of the patients in our study.…”

“…The stimulation of a primary naive T‐cell response stresses the functional capacity of those cells. Induction of specific antileukemic T‐cell activity by priming with leukemic DC was reported by other investigators [9]. We tried to reduce the influence of contaminating B cells and monocytes by performing fluorescence‐activated or immunomagnetic enrichment of CD1a + /CD14 – DC to a purity of more than 80%.…”

“…The sorted fractions of five AML patients have provided evidence for the differentiation of leukemic stem cells into DC with different maturation grades. FISH analysis of unselected cultures performed by other groups might be clouded by the mixture of different cells in the samples [9].…”

“…DC presenting leukemic antigens seem to be potent effectors for induction of cytotoxic T cell responses in vivo or in vitro [7]. Only recently two groups have suggested that DC with the leukemic genotype or leukemia‐specific antigen markers can be grown in vitro out of AML cells [8, 9]. Those DC were able to induce specific cytotoxicity of autologous T cells against leukemic target cells.…”

Modulation of antitumor immune responses by hematopoietic cytokines

“…70 Myeloid progenitors obtained from patients with AML differentiated to enhanced antigenpresenting cells when treated in vitro with GM-CSF, TNF, IL-4, CD40 ligand, Flt3, or SCF. 71 Likewise, others have reported similar results after GM-CSF, TNF, and IL-4 culture of cells obtained from patients with AML and CML; 72,73 and Coleman et al reported the restoration of costimulatory molecules on GM-CSF and IL-4-incubated T-cells obtained from patients with CML. 74 In a series of interrelated trials reported by Bedi et al and Jones et al, CML progenitor cells were eliminated preferentially from culture through terminal differentiation in the presence of hematopoietic growth factors.…”