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Lopez, Annika Hirn; Deen, Diana; Fischer, Zuzanna; Rabe, Alexander; Ansprenger, Christian; Stein, Kathy; Vogt, Valentin; Schick, Julia; Kroell, Tanja; Krämer, Doris; Kolb, Hans-Jochem; Tischer, Johanna; Schmid, Christoph; Schmetzer, Helga (2019): Role of Interferon (IFN)alpha in "Cocktails" for the Generation of (Leukemia-derived) Dendritic Cells (DCleu) From Blasts in Blood From Patients (pts) With Acute Myeloid Leukemia (AML) and the Induction of Antileukemic Reactions. In: Journal of Immunotherapy, Vol. 42, No. 5: pp. 143-161
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Abstract

Strategies to stabilize remissions by specific elimination of residual acute myeloid leukemia (AML) blasts are needed. Leukemia-derived dendritic cell (DCleu/DC) generated from myeloid blasts improve antileukemic T-cell reactivity and install T-cell memory. Interferon (IFN)alpha-DC methods produce DCleu from chronic myeloid leukemia-patients (pts') blood. Various INF alpha-containing versus other DC methods were studied to produce DCleu (evaluated by flowcytometry) from AML-pts' blast-containing mononuclear (MNC) or whole blood (WB). After DCleu/DC stimulation in mixed lymphocyte cultures, T cells' potential to gain antileukemic cytotoxicity was studied and correlated with different DC methods and DCleu/DC counts. (1) Generation of DCleu/DC: (a) "IFN-GIT" [containing granulocyte macrophage-colony stimulating factor (GM-CSF)+IFN alpha+ tumor necrosis factor (TNF)-alpha] produced DC successfully (>= 10% DC, >= 5% DCleu/cells) from AML-MNC (WB) in 54 (56%), "MCM-Mimic" in 76 (75%), "Picibanil" in 83 (64%), and "Calcium-ionophore" in 42 (67%) of cases. Proportions of DC subtypes in MNC (WB) were comparable with all DC methods, (b) IFN alpha combinations containing only GM-CSF+IFN alpha or only IFN alpha showed low efficiency to produce DCleu/DC from MNC (WB) compared with "IFN-GIT." (2) Antileukemic functionality: DCleu/DC-stimulated T cells showed improved leukemia cytotoxicity compared with blast cells or unstimulated T cells. The highest blast proliferation (=insufficient T cells) was seen with "IFN-GIT" DC-stimulated T cells. Probability to respond to immunotherapy or to obtain blast lysis of DC-stimulated T cells correlated with high proportions of DCleu/DC after DC culture, independent of DC-generating methods. (3) Cytokine release profiles: levels of interleukin-6, IFN-gamma, and interleukin-2 were significantly lower in DC culture supernatants (from MNC/WB) with "IFN-GIT" compared with "MCM," "Pici," and "Ca" DC supernatants. Our data show that (1) WB culture simulates AML-pts' in vivo situation, (2) DC generation is possible from AML-MNC (WB) with IFN alpha-containing and other DC methods, (3) successful IFN alpha-DC generation needs GM-CSF+IFN alpha+TNF-alpha (IFN-GIT);however, "IFN-GIT" produces less DCleu/DC compared with other (non-IFN alpha) DC methods, (4) T cells stimulated with "IFN-GIT"-produced DCleu/DC yielded comparable antileukemic cytotoxicity;however, in cases without achieved blast lysis, an increased blast proliferation was observed.