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Immunotherapy versus Immune Modulation of Leukemia

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 May 2024) | Viewed by 1716

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Prof. Dr. Helga Maria Schmetzer

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Med III, Department for Hematopoetic Transplantations, Klinikum Grosshadern, Ludwig-Maximilian-University of Munich, Marchioninistrße 15, 81377 Munich, Germany
Interests: dendritic cells; leukemia derived DC; AML; immunotherapy
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Dear Colleagues,

Most patients with acute myeloid leukemia (AML) initially respond to chemotherapy; however, 80% of patients relapse soon after due to reoccurring blasts.

Besides allogeneic standard stem cell transplantation antibodies (e.g targeting checkpoint molecules) and cellular CAR-T or -NK, cell immunotherapeutic strategies aim to overcome the problem of the few available neoantigens in AML. Extracellular vesicles (carrying signaling molecules or RNA cargo) are being tested for antileukemic activity. In addition, pharmacological immune modulating strategies influencing cell proliferation, apoptosis, and signal transducing pathways are being tested to overcome drug resistance and sensitize blasts to chemotherapy.

Engineered or leukemia-derived dendritic cells (DCs/DCleu) link the adaptive and innate immunity and mediate blast killing ex vivo and in vivo. Drug-induced DCleu from blasts in vivo could stabilize remissions or the disease in AML patients via induced immune modulation

Here, we summarize immunotherapies that are needed to destroy leukemic cells and (immune) modulating strategies to change the cellular/soluble microenvironment into an “antileukemic environment” stabilize antileukemic processes, and overcome resistance.

Prof. Dr. Helga Maria Schmetzer
Guest Editor

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Keywords

leukemia
immunotherapy
immune modulation
antileukemic
drug resistance

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Research

24 pages, 3835 KiB

Open AccessArticle

Effective and Successful Quantification of Leukemia-Specific Immune Cells in AML Patients’ Blood or Culture, Focusing on Intracellular Cytokine and Degranulation Assays

by Olga Schutti, Lara Klauer, Tobias Baudrexler, Florian Burkert, Joerg Schmohl, Marcus Hentrich, Peter Bojko, Doris Kraemer, Andreas Rank, Christoph Schmid and Helga Schmetzer

Int. J. Mol. Sci. 2024, 25(13), 6983; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25136983 - 26 Jun 2024

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Abstract

Novel (immune) therapies are needed to stabilize remissions or the disease in AML. Leukemia derived dendritic cells (DCleu) can be generated ex vivo from AML patients’ blasts in whole blood using approved drugs (GM-CSF and PGE-1 (Kit M)). After T cell enriched, mixed lymphocyte culture (MLC) with Kit M pretreated (vs. untreated WB), anti-leukemically directed immune cells of the adaptive and innate immune systems were already shown to be significantly increased. We evaluated (1) the use of leukemia-specific assays [intracellular cytokine production of INFy, TNFa (INCYT), and degranulation detected by CD107a (DEG)] for a detailed quantification of leukemia-specific cells and (2), in addition, the correlation with functional cytotoxicity and patients’ clinical data in Kit M-treated vs. not pretreated settings. We collected whole blood (WB) samples from 26 AML patients at first diagnosis, during persisting disease, or at relapse after allogeneic stem cell transplantation (SCT), and from 18 healthy volunteers. WB samples were treated with or without Kit M to generate DC/DCleu. After MLC with Kit M-treated vs. untreated WB antigen-specific/anti-leukemic effects were assessed through INCYT, DEG, and a cytotoxicity fluorolysis assay. The quantification of cell subtypes was performed via flow cytometry. Our study showed: (1) low frequencies of leukemia-specific cells (subtypes) detectable in AML patients’ blood. (2) Significantly higher frequencies of (mature) DCleu generable without induction of blast proliferation in Kit M-treated vs. untreated samples. (3) Significant increase in frequencies of immunoreactive cells (e.g., non-naive T cells, Tprol) as well as in INCYT/DEG ASSAYS leukemia-specific adaptive—(e.g., B, T(memory)) or innate immune cells (e.g., NK, CIK) after MLC with Kit M-treated vs. untreated WB. The results of the intracellular production of INFy and TNFa were comparable. The cytotoxicity fluorolysis assay revealed significantly enhanced blast lysis in Kit M-treated vs. untreated WB. Significant correlations could be shown between induced leukemia-specific cells from several lines and improved blast lysis. We successfully detected and quantified immunoreactive cells at a single-cell level using the functional assays (DEG, INCYT, and CTX). We could quantify leukemia-specific subtypes in uncultured WB as well as after MLC and evaluate the impact of Kit M pretreated (DC/DCleu-containing) WB on the provision of leukemia-specific immune cells. Kit M pretreatment (vs. no pretreatment) was shown to significantly increase leukemia-specific IFNy and TNFa producing, degranulating cells and to improve blast-cytotoxicity after MLC. In vivo treatment of AML patients with Kit M may lead to anti-leukemic effects and contribute to stabilizing the disease or remissions. INCYT and DEG assays qualify to quantify potentially leukemia-specific cells on a single cell level and to predict the clinical course of patients under treatment. Full article

(This article belongs to the Special Issue Immunotherapy versus Immune Modulation of Leukemia)

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26 pages, 3699 KiB

Open AccessArticle

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

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

Int. J. Mol. Sci. 2023, 24(24), 17436; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242417436 - 13 Dec 2023

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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 (DC_leu). After stimulation with DC_leu 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/DC_leu. 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) DC_leu 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 (T_reg, 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 DC_leu, (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 DC_leu 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. Full article

(This article belongs to the Special Issue Immunotherapy versus Immune Modulation of Leukemia)

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