Stimulation of autologous proliferative and cytotoxic T-cell responses by “leukemic dendritic cells” derived from blast cells in acute myeloid leukemia

Abstract

Effective presentation of tumor antigens is fundamental to strategies aimed at enrolling the immune system in eradication of residual disease after conventional treatments. Myeloid malignancies provide a unique opportunity to derive dendritic cells (DCs), functioning antigenpresenting cells, from the malignant cells themselves. These may then co-express leukemic antigens together with appropriate secondary signals and be used to generate a specific, antileukemic immune response. In this study, blasts from 40 patients with acute myeloid leukemia (AML) were cultured with combinations of granulocyte-macrophage colony-stimulating factor, interleukin 4, and tumor necrosis factor ␣, and development to DCs was assessed. After culture, cells from 24 samples exhibited morphological and immunophenotypic features of DCs, including expression of major histocompatibility complex class II, CD1a, CD83, and CD86, and were potent stimulators in an allogeneic mixed lymphocyte reaction (MLR). Stimulation of autologous T-cell responses was assessed by the proliferative response of autologous T cells to the leukemic DCs and by demonstration of the induction of specific, autologous, antileukemic cytotoxicity. Of 17 samples, 11 were effective stimulators in the autologous MLR, and low, but consistent, autologous, antileukemic cytotoxicity was induced in 8 of 11 cases (mean, 27%; range, 17%-37%). This study indicates that cells with enhanced antigen-presenting ability can be generated from AML blasts, that these cells can effectively prime autologous cytotoxic T cells in vitro, and that they may be used as potential vaccines in the immunotherapy of AML. (Blood. 2001; 97:2764-2771)

Generation of immunostimulatory dendritic cells from the malignant clone in patients with juvenile myelomonocytic leukemia

“…On the other hand, the autoimmune polyendocrine syndrome (APS) is defined as the occurrence of several autoimmune diseases of the endocrine system in the same patient. 1 Two types of APS have been described. The autoimmune polyendocrine syndrome type II (APS II) syndrome most frequently associates with autoimmune thyroid disorders (AITD), Addison's disease and Type I diabetes.…”

“…These leukemic DC have potential therapeutic applications, such as stimulation of autologous anti leukemia T-cell responses in leukemia patients, or allogeneic responses in the post bone marrow transplantation (BMT) setting. Several studies have demonstrated that leukemic cells from a proportion of patients with acute myeloid leukemia (AML) 1 or chronic myeloid leukemia (CML) 2 can be differentiated into functionally active DC capable of inducing antileukemia T-cell responses. 3,4 We were interested in the utilization of such an immunotherapeutic approach for patients with juvenile myelomonocytic leukemia (JMML), a rare condition with poor prognosis.…”

Primary acute myeloid leukaemia blasts resistant to cytokine-induced differentiation to dendritic-like leukaemia cells can be forced to differentiate by the addition of bryostatin-1

“…These DLLC share many features in common with monocyte-derived dendritic cells (MDDC) in that they express the costimulatory molecules CD40, CD80 and CD86 and the dendritic cell-associated molecule CD83, [1][2][3][4][5][6][7][8][9] secrete the immunostimulatory cytokine IL-12 3 and are potent stimulators of allogeneic T lymphocytes in mixed leukaemia lymphocyte reactions (MLLR). [1][2][3][4][5][6]9 Importantly, it has been demonstrated that autologous cytotoxic T lymphocytes, capable of recognising and destroying unmodified leukaemia cells, can be generated by co-culturing T cells with autologous DLLC. 3,4,6 Based on this ability to present putative leukaemia-specific antigens to autologous T cells, DLLC might offer potential as vaccines for the treatment of AML.…”

Dendritic cells in MDS and AML – cause, effect or solution to the immune pathogenesis of disease?

“…20 In the blood of patients with MDS, 21 there is an oligoclonal dominance of T cells with a cytotoxic profile, suggesting specific response to a set of disease-related antigens. The evaluation of lymphocyte function in AML has primarily assessed anti-leukaemia cytotoxic T lymphocytes (CTL) expanded in vitro, with the use of IL-2 or phytohaemagglutinin, from the peripheral blood of patients with AML and CML, who have achieved a chemotherapy-induced remission, 5,22 as well as in those patients with fulminant disease. 23 WT1-specific CTL 17 and antibodies can also be detected in patients with active AML.…”

“…When considering these problems, as well as the fact that approximately 60-80% of primary AML samples may generate DC in in vitro culture, one might classify AML, and MDS, as a type of bone marrow malignancy derived from DC precursors. These AML-derived DC (AML-DC) arise from the leukaemic clone [3][4][5] and, thus, may express leukaemic antigens. Hence, AMLspecific and patient-specific AML-DC may be generated for potential use in the immune therapy of AML.…”