Use of leukemic dendritic cells for the generation of antileukemic cellular cytotoxicity against Philadelphia chromosome-positive chronic myelogenous leukemia.
The success of adoptive immunotherapy for the treatment of leukemia depends on the generation of T cells that can specifically react with malignant cells. Dendritic cells (DCs) are important antigen-presenting cells in the development of antileukemic T-cell responses. In this study, we generated DCs from peripheral blood cells of patients with chronic myelogenous leukemia (CML). CML cells incubated concurrently with granulocyte-macrophage colony-stimulating factor, interleukin-4, and tumor necrosis factor-alpha in vitro developed morphologic and phenotypic characteristics of DCs. Fluorescence in situ hybridization showed the presence of t(9;22) in the nuclei of these cells, indicating that they were leukemic in origin. These cells were potent stimulators of lymphocyte proliferation in specific in vitro assays for DC function. Autologous T cells stimulated with in vitro-generated, leukemic DCs displayed vigorous cytotoxic activity against CML cells but low reactivity to major histocompatability complex-matched normal bone marrow cells. Cytotoxic activity against CML targets was fourfold to sixfold higher using DC-stimulated autologous T cells than with autologous T cells expanded by culture with interleukin-2 alone. DC-stimulated T cells also inhibited growth of CML clonogenic precursors in colony-forming assays in vitro. These results suggest that cytokine-driven in vitro differentiation of CML cells results in generation of DCs with potent T-cell stimulatory function. In vitro-generated DCs can be effectively used as antigen-presenting cells for the ex vivo expansion of antileukemic T cells.
Choudhury
A
A
Department of Hematology and Laboratory Medicine, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Gajewski
J L
JL
Liang
J C
JC
Popat
U
U
Claxton
D F
DF
Kliche
K O
KO
Andreeff
M
M
Champlin
R E
RE
D002454:Cell Differentiation / Q000187:drug effects; D018920:Coculture Techniques; D016207:Cytokines / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D016130:Immunophenotyping; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology*; D015466:Leukemia, Myeloid, Chronic-Phase / Q000276:immunology*; D008213:Lymphocyte Activation; D014411:Neoplastic Stem Cells / Q000276:immunology* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014410:Tumor Stem Cell Assay
D016207:Cytokines; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor