Interferon alpha in combination with GM‐CSF induces the differentiation of leukaemic antigen‐presenting cells that have the capacity to stimulate a specific anti‐leukaemic cytotoxic T‐cell response from patients with chronic myeloid leukaemia

Although interferon α (IFN‐α) is able to induce haematological remission in 60–80% of patients with chronic myeloid leukaemia (CML) in early chronic phase, major cytogenetic remissions are only achievable in 30–40%. Recent clinical data suggest that the addition of granulocyte–macrophage colony‐stimulating factor (GM‐CSF) to IFN‐α therapy can significantly improve the cytogenetic response in some patients, although the mechanism remains unknown. We hypothesized that the combination of GM‐CSF and IFN‐α induces the differentiation of dendritic cells, which subsequently stimulates a specific anti‐leukaemic response. Monocytes from CML patients were cultured in GM‐CSF and interleukin (IL)‐4 (GM/IL‐4)or in GM‐CSF and IFN‐α (GM/IFN‐α). After 7 d, the number of cells exhibiting typical antigen‐presenting cell (APC) morphology was equal in both groups, and fluorescence in situ hybridization (FISH) analysis confirmed that the APCs generated with GM/IFN‐α were of leukaemic origin. Phenotypically, both sets of APCs expressed typical surface markers; however, CD86, CD83, CD11c, HLA‐ABC and HLA‐DR expression was significantly higher in the GM/IFN‐α APCs, whereas CD1a expression was significantly lower. In mixed lymphocyte reactions (MLR), GM/IFN‐α APCs stimulated the proliferation of allogeneic T cells significantly better than GM/IL‐4 APCs. However, both groups of APCs stimulated autologous T‐cell proliferation equally. Finally, we assessed the ability of GM/IFN‐α APCs to induce a leukaemia‐specific cytotoxic T‐cell response. Some samples generated cytotoxic T lymphocytes (CTLs) that specifically lysed bcr‐abl‐positive target cells. These data show that the combination of GM‐CSF and IFN‐α, when used in vitro, induces the differentiation of malignant APCs with potent T‐cell stimulatory capacity. Although there is no in vivo evidence to support these findings, it is possible that, when administered to CML patients, GM‐CSF in combination with IFN‐α results in the generation of highly stimulatory leukaemic APCs.