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. 2023 Dec 13;24(24):17436.
doi: 10.3390/ijms242417436.

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

Marianne Unterfrauner  1 , Hazal Aslan Rejeski  1 , Anne Hartz  1 , Sophia Bohlscheid  1 , Tobias Baudrexler  1 , Xiaojia Feng  1 , Elias Rackl  1 , Lin Li  1 , Andreas Rank  2 , Giuliano Filippini Velázquez  2 , Christoph Schmid  2 , Jörg Schmohl  3 , Peter Bojko  4 , Helga Schmetzer  1
Affiliations

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

Marianne Unterfrauner et al. Int J Mol Sci. .

Abstract

Although several (chemotherapeutic) protocols to treat acute myeloid leukemia (AML) are available, high rates of relapses in successfully treated patients occur. Strategies to stabilize remissions are greatly needed. The combination of the (clinically approved) immune-modulatory compounds Granulocyte-Macrophage-Colony-Stimulating-Factor (GM-CSF) and Prostaglandine E1 (PGE-1) (Kit-M) converts myeloid blasts into dendritic cells of leukemic origin (DCleu). After stimulation with DCleu ex vivo, leukemia-specific antileukemic immune cells are activated. Therefore, Kit-M treatment may be an attractive immunotherapeutic tool to treat patients with myeloid leukemia. Kit-M-mediated antileukemic effects on whole bone marrow (WBM) were evaluated and compared to whole blood (WB) to evaluate the potential effects of Kit-M on both compartments. WB and WBM samples from 17 AML patients at first diagnosis, in persisting disease and at relapse after allogeneic stem cell transplantation (SCT) were treated in parallel with Kit-M to generate DC/DCleu. Untreated samples served as controls. After a mixed lymphocyte culture enriched with patients' T cells (MLC), the leukemia-specific antileukemic effects were assessed through the degranulation- (CD107a+ T cells), the intracellular IFNγ production- and the cytotoxicity fluorolysis assay. Quantification of cell subtypes was performed via flow cytometry. In both WB and WBM significantly higher frequencies of (mature) DCleu were generated without induction of blast proliferation in Kit-M-treated samples compared to control. After MLC with Kit-M-treated vs. not pretreated WB or WBM, frequencies of (leukemia-specific) immunoreactive cells (e.g., non-naive, effector-, memory-, CD3+β7+ T cells, NK- cells) were (significantly) increased, whereas leukemia-specific regulatory T cells (Treg, CD152+ T cells) were (significantly) decreased. The cytotoxicity fluorolysis assay showed a significantly improved blast lysis in Kit-M-treated WB and WBM compared to control. A parallel comparison of WB and WBM samples revealed no significant differences in frequencies of DCleu, (leukemia-specific) immunoreactive cells and achieved antileukemic processes. Kit-M was shown to have comparable effects on WB and WBM samples regarding the generation of DCleu and activation of (antileukemic) immune cells after MLC. This was true for samples before or after SCT. In summary, a potential Kit-M in vivo treatment could lead to antileukemic effects in WB as well as WBM in vivo and to stabilization of the disease or remission in patients before or after SCT. A clinical trial is currently being planned.

Keywords: AML; dendritic cell-based therapy; immune escape; leukemia-derived dendritic cells; whole blood; whole bone marrow.

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Conflict of interest statement

H.M.S. is involved with Modiblast Pharma GmbH (Oberhaching, Germany), which holds the European Patent 15 801 987.7-1118 and US Patent 15-517627, “Use of immunomod-ulatory effective compositions for the immunotherapeutic treatment of patients suffering from myeloid leukemias”.

Figures

Figure 1
Figure 1
Composition of T and Innate Immune Cell Subtypes in Uncultured WB and WBM.
Figure 2
Figure 2
Composition of Leukemia-Specific Degranulating (A) or IFNγ-Secreting (B) Immunoreactive Cells in Uncultured WB and WBM.
Figure 3
Figure 3
Effects of Kit-M on the Generation of (Mature) DC/DCleu referred to WB (A) or Blasts (B) and on Blast Proliferation (A) in Leukemic WB and WBM.
Figure 4
Figure 4
Effects of Kit-M-Treated WB and WBM on the Provision of Immunoreactive Cells After T cell-enriched Mixed Lymphocyte Culture (MLC).
Figure 5
Figure 5
Effects of Kit-M-Treated WB and WBM on the Degranulation Activity of T cells After MLC.
Figure 6
Figure 6
Effects of Kit-M-Treated WB and WBM on the Intracellular IFNγ Production of T cells After MLC.
Figure 7
Figure 7
Effects of Kit-M-Treated WB and WBM on the Antileukemic Activity after MLC including Cases with Lysis (A), Cytotoxicity (B), Cases with Improved Lysis (C) and Improved Cytotoxicity (D).
Figure 7
Figure 7
Effects of Kit-M-Treated WB and WBM on the Antileukemic Activity after MLC including Cases with Lysis (A), Cytotoxicity (B), Cases with Improved Lysis (C) and Improved Cytotoxicity (D).
Figure 8
Figure 8
Cases with Improved Lysis in Patient Samples Subdivided into Risk Groups (A) and Response to Induction Chemotherapy (B) at First Diagnosis.
Figure 9
Figure 9
Effects of Kit-M or GM-CSF-Treated WB (A) and WBM (B) on Platelet Counts.
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