Potential of immunotherapies in the mediation of antileukemic responses for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) - With a focus on Dendritic cells of leukemic origin (DC(leu)).

New (non-immunotherapeutic) treatment-strategies for AML/MDS-patients are under development. Dendritic cells (DCs) and 'leukemia-derived DC' (DCleu) connect the innate and the adaptive immunesystem and (re-)activate it, in their capacity as professional antigen-presenting cells (APCs). They can be generated ex vivo from peripheral blood mononuclear cells (PBMNCs) or whole blood (WB), containing the -physiological-cellular/soluble microenvironment of individual patients using various DC/DCleu-generating methods or (for WB) minimalized 'Kits', containing granulocyte-macrophage-colony-stimulating-factor (GM-CSF) and a second response-modifier. Proof for DC/DCleu-mediated activation of the immune-system after T-cell-enriched mixed lymphocyte culture (MLC) is done by flowcytometry, demonstrating increased fractions of certain activated, leukemia-specific or antileukemic cell-subsets of the innate and the adaptive immune-system. Generation of DC/DCleu is possible independent of patients' age, MHC-, mutation- or transplantation-status. In vivo-treatment of AML-/MDS-patients with blast-modulating, DC/DCleu- inducing 'Kits' could contribute to create migratory DCs, as well as antileukemically reactivated and memory-mediating immune-cells, which patrol tissue and blood and could contribute to stabilizing disease or remissions.

Ansprenger C ，Amberger DC ，Schmetzer HM 《-》

Role of Interferon (IFN)α 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.

Hirn Lopez A ，Deen D ，Fischer Z ，Rabe A ，Ansprenger C ，Stein K ，Vogt V ，Schick J ，Kroell T ，Kraemer D ，Kolb HJ ，Tischer J ，Schmid C ，Schmetzer H ... -  《-》

Granulocyte-Macrophage-Colony-Stimulating-Factor Combined with Prostaglandin E1 Create Dendritic Cells of Leukemic Origin from AML Patients' Whole Blood and Whole Bone Marrow That Mediate Antileukemic Processes after Mixed Lymphocyte Culture.

Unterfrauner M ，Rejeski HA ，Hartz A ，Bohlscheid S ，Baudrexler T ，Feng X ，Rackl E ，Li L ，Rank A ，Filippini Velázquez G ，Schmid C ，Schmohl J ，Bojko P ，Schmetzer H ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

Serum-free generation and quantification of functionally active Leukemia-derived DC is possible from malignant blasts in acute myeloid leukemia and myelodysplastic syndromes.

Kufner S ，Fleischer RP ，Kroell T ，Schmid C ，Zitzelsberger H ，Salih H ，de Valle F ，Treder W ，Schmetzer HM ... -  《-》

Conversion of AML-blasts to leukemia-derived dendritic cells (DCleu) in 'DC-culture-media' shifts correlations of released chemokines with antileukemic T-cell reactions.

Dendritic cells (DC) and T-cells are mediators of CTL-responses. Autologous (from patients with acute myeloid leukaemia (AML) or myelodysplasia (MDS)) or allogeneic (donor)-T-cells stimulated by DCleu, gain an efficient lysis of naive blasts, although not in every case. CXCL8, -9, -10, CCL2, -5 and Interleukin (IL-12) were quantified by Cytometric Bead Array (CBA) in supernatants from 5 DC-generating methods and correlated with AML-/MDS-patients' serum-values, DC-/T-cell-interactions/antileukemic T-cell-reactions after mixed lymphocyte culture (MLC) and patients' clinical course. The blast-lytic activity of T-cells stimulated with DC or mononuclear cells (MNC) was quantified in a cytotoxicity assay. Despite great variations of chemokine-levels, correlations with post-stimulation (after stimulating T-cells with DC in MLC) improved antileukemic T-cell activity were seen: higher released chemokine-values correlated with improved T-cells' antileukemic activity (compared to stimulation with blast-containing MNC) - whereas with respect to the corresponding serum values higher CXCL8-, -9-, and -10- but lower CCL5- and -2-release correlated with improved antileukemic activity of DC-stimulated (vs. blast-stimulated) T-cells. In DC-culture supernatants higher chemokine-values correlated with post-stimulation improved antileukemic T-cell reactivity, whereas higher serum-values of CXCL8, -9, and -10 but lower serum-values of CCL5 and -2 correlated with post-stimulation improved antileukemic T-cell-reactivity. In a context of 'DC'-stimulation (vs serum) this might point to a change of (CCL5 and -2-associated) functionality from a more 'inflammatory' or 'tumor-promoting' to a more 'antitumor'-reactive functionality. This knowledge could contribute to develop immune-modifying strategies that promote antileukemic (adaptive) immune-responses.

Merle M ，Fischbacher D ，Liepert A ，Grabrucker C ，Kroell T ，Kremser A ，Dreyssig J ，Freudenreich M ，Schuster F ，Borkhardt A ，Kraemer D ，Koehne CH ，Kolb HJ ，Schmid C ，Schmetzer HM ... -  《-》