Editorial

4 pages, 149 KiB

Open AccessEditorial

The Important Role of Immunotherapies in Acute Myeloid Leukemia

by Jochen Greiner

J. Clin. Med. 2019, 8(12), 2054; https://doi.org/10.3390/jcm8122054 - 22 Nov 2019

Cited by 5 | Viewed by 1899

This series on immunotherapies in acute myeloid leukemia (AML) aims to give readers new insights on established but also emerging immunotherapeutic approaches for AML patients [...] Full article

(This article belongs to the Special Issue Immunotherapies for Acute Myeloid Leukemia)

Research

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20 pages, 2900 KiB

Open AccessArticle

High Constitutive Cytokine Release by Primary Human Acute Myeloid Leukemia Cells Is Associated with a Specific Intercellular Communication Phenotype

by Håkon Reikvam, Elise Aasebø, Annette K. Brenner, Sushma Bartaula-Brevik, Ida Sofie Grønningsæter, Rakel Brendsdal Forthun, Randi Hovland and Øystein Bruserud

J. Clin. Med. 2019, 8(7), 970; https://doi.org/10.3390/jcm8070970 - 04 Jul 2019

Cited by 23 | Viewed by 2860

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease, and this heterogeneity includes the capacity of constitutive release of extracellular soluble mediators by AML cells. We investigated whether this capacity is associated with molecular genetic abnormalities, and we compared the proteomic profiles of AML [...] Read more.

Acute myeloid leukemia (AML) is a heterogeneous disease, and this heterogeneity includes the capacity of constitutive release of extracellular soluble mediators by AML cells. We investigated whether this capacity is associated with molecular genetic abnormalities, and we compared the proteomic profiles of AML cells with high and low release. AML cells were derived from 71 consecutive patients that showed an expected frequency of cytogenetic and molecular genetic abnormalities. The constitutive extracellular release of 34 soluble mediators (CCL and CXCL chemokines, interleukins, proteases, and protease regulators) was investigated for an unselected subset of 62 patients, and they could be classified into high/intermediate/low release subsets based on their general capacity of constitutive secretion. FLT3-ITD was more frequent among patients with high constitutive mediator release, but our present study showed no additional associations between the capacity of constitutive release and 53 other molecular genetic abnormalities. We compared the proteomic profiles of two contrasting patient subsets showing either generally high or low constitutive release. A network analysis among cells with high release levels demonstrated high expression of intracellular proteins interacting with integrins, RAC1, and SYK signaling. In contrast, cells with low release showed high expression of several transcriptional regulators. We conclude that AML cell capacity of constitutive mediator release is characterized by different expression of potential intracellular therapeutic targets. Full article

(This article belongs to the Special Issue Immunotherapies for Acute Myeloid Leukemia)

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Review

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22 pages, 629 KiB

Open AccessReview

Immunological and Clinical Impact of Manipulated and Unmanipulated DLI after Allogeneic Stem Cell Transplantation of AML Patients

by Jochen Greiner, Marlies Götz, Donald Bunjes, Susanne Hofmann and Verena Wais

J. Clin. Med. 2020, 9(1), 39; https://doi.org/10.3390/jcm9010039 - 23 Dec 2019

Cited by 22 | Viewed by 4056

Abstract

Allogeneic stem cell transplantation (allo-SCT) is the preferred curative treatment for several hematological malignancies. The efficacy of allo-SCT depends on the graft-versus-leukemia (GvL) effect. However, the prognosis of patients with relapsed acute myeloid leukemia (AML) following allo-SCT is poor. Donor lymphocyte infusion (DLI) [...] Read more.

Allogeneic stem cell transplantation (allo-SCT) is the preferred curative treatment for several hematological malignancies. The efficacy of allo-SCT depends on the graft-versus-leukemia (GvL) effect. However, the prognosis of patients with relapsed acute myeloid leukemia (AML) following allo-SCT is poor. Donor lymphocyte infusion (DLI) is utilized after allo-SCT in this setting to prevent relapse, to prolong progression free survival, to establish full donor chimerism and to restore the GvL effect in patients with hematological malignancies. Thus, there are different options for the administration of DLI in AML patients. DLI is currently used prophylactically and in the setting of an overt relapse. In addition, in the minimal residual disease (MRD) setting, DLI may be a possibility to improve overall survival. However, DLI might increase the risk of severe life-threatening complications such as graft-versus-host disease (GvHD) as well as severe infections. The transfusion of lymphocytes has been tested not only for the treatment of hematological malignancies but also chronic infections. In this context, manipulated DLI in a prophylactic or therapeutic approach are an option, e.g., virus-specific DLI using different selection methods or antigen-specific DLI such as peptide-specific CD8+ cytotoxic T lymphocytes (CTLs). In addition, T cells are also genetically engineered, using both chimeric antigen receptor (CAR) genetically modified T cells and T cell receptor (TCR) genetically modified T cells. T cell therapies in general have the potential to enhance antitumor immunity, augment vaccine efficacy, and limit graft-versus-host disease after allo-SCT. The focus of this review is to discuss the different strategies to use donor lymphocytes after allo-SCT. Our objective is to give an insight into the functional effects of DLI on immunogenic antigen recognition for a better understanding of the mechanisms of DLI. To ultimately increase the GvL potency without raising the risk of GvHD at the same time. Full article

(This article belongs to the Special Issue Immunotherapies for Acute Myeloid Leukemia)

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13 pages, 2780 KiB

Open AccessReview

FLAMSA-RIC for Stem Cell Transplantation in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndromes: A Systematic Review and Meta-Analysis

by Weerapat Owattanapanich, Patompong Ungprasert, Verena Wais, Smith Kungwankiattichai, Donald Bunjes and Florian Kuchenbauer

J. Clin. Med. 2019, 8(9), 1437; https://doi.org/10.3390/jcm8091437 - 11 Sep 2019

Cited by 9 | Viewed by 3874

Abstract

Reduced-intensity conditioning (RIC) regimens are established options for hematopoietic stem cell transplantation (HSCT) for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, the efficacy of RIC regimens for patients with high-risk disease is limited. The addition of a fludarabine, amsacrine, [...] Read more.

Reduced-intensity conditioning (RIC) regimens are established options for hematopoietic stem cell transplantation (HSCT) for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, the efficacy of RIC regimens for patients with high-risk disease is limited. The addition of a fludarabine, amsacrine, and cytarabine (FLAMSA)-sequential conditioning regimen was introduced for patients with high-risk MDS and AML to combine a high anti-leukemic activity with the advantages of RIC. The current systematic literature review and meta-analysis was conducted with the aim of identifying all cohort studies of patients with AML and/or MDS who received FLAMSA-RIC to determine its efficacy and toxicity. Out of 3044 retrieved articles, 12 published studies with 2395 overall patients (18.1–76.0 years; 96.8% AML and 3.2% MDS; follow-up duration of 0.7–145 months; 50.3% had active AML disease before HSCT) met the eligibility criteria and were included in the meta-analysis. In the pooled analysis, the 1- and 3-year overall survival (OS) rates were 59.6% (95% confidence interval (CI), 47.9–70.2%) and 40.2% (95% CI, 28.0–53.7%), respectively. The pooled 3-year OS rate of the patients who achieved CR1 or CR2 prior to HSCT was 60.1% (95% CI, 55.1–64.8%) and the percentage of those with relapse or refractory disease was 27.8% (95% CI, 23.3–32.8%). The pooled 3-year leukemia-free survival (LFS) rate was 39.3% (95% CI, 26.4–53.9%). Approximately 29% of the patients suffered from grades 2–4 acute graft-versus-host disease (GVHD), while 35.6% had chronic GVHD. The pooled 1- and 3-year non-relapse mortality (NRM) rates were 17.9% (95% CI, 16.1–19.8%) and 21.1% (95% CI, 18.8–23.7%), respectively. Our data indicates that the FLAMSA-RIC regimen is an effective and well-tolerated regimen for HSCT in patients with high-risk AML and MDS. Full article

(This article belongs to the Special Issue Immunotherapies for Acute Myeloid Leukemia)

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31 pages, 971 KiB

Open AccessReview

Antibody Therapies for Acute Myeloid Leukemia: Unconjugated, Toxin-Conjugated, Radio-Conjugated and Multivalent Formats

by Brent A. Williams, Arjun Law, Judit Hunyadkurti, Stephanie Desilets, Jeffrey V. Leyton and Armand Keating

J. Clin. Med. 2019, 8(8), 1261; https://doi.org/10.3390/jcm8081261 - 20 Aug 2019

Cited by 37 | Viewed by 6809

Abstract

In recent decades, therapy for acute myeloid leukemia (AML) has remained relatively unchanged, with chemotherapy regimens primarily consisting of an induction regimen based on a daunorubicin and cytarabine backbone, followed by consolidation chemotherapy. Patients who are relapsed or refractory can be treated with [...] Read more.

In recent decades, therapy for acute myeloid leukemia (AML) has remained relatively unchanged, with chemotherapy regimens primarily consisting of an induction regimen based on a daunorubicin and cytarabine backbone, followed by consolidation chemotherapy. Patients who are relapsed or refractory can be treated with allogeneic hematopoietic stem-cell transplantation with modest benefits to event-free and overall survival. Other modalities of immunotherapy include antibody therapies, which hold considerable promise and can be categorized into unconjugated classical antibodies, multivalent recombinant antibodies (bi-, tri- and quad-specific), toxin-conjugated antibodies and radio-conjugated antibodies. While unconjugated antibodies can facilitate Natural Killer (NK) cell antibody-dependent cell-mediated cytotoxicity (ADCC), bi- and tri-specific antibodies can engage either NK cells or T-cells to redirect cytotoxicity against AML targets in a highly efficient manner, similarly to classic ADCC. Finally, toxin-conjugated and radio-conjugated antibodies can increase the potency of antibody therapies. Several AML tumour-associated antigens are at the forefront of targeted therapy development, which include CD33, CD123, CD13, CLL-1 and CD38 and which may be present on both AML blasts and leukemic stem cells. This review focused on antibody therapies for AML, including pre-clinical studies of these agents and those that are either entering or have been tested in early phase clinical trials. Antibodies for checkpoint inhibition and microenvironment targeting in AML were excluded from this review. Full article

(This article belongs to the Special Issue Immunotherapies for Acute Myeloid Leukemia)

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14 pages, 722 KiB

Open AccessReview

Dendritic Cell-Based Immunotherapy of Acute Myeloid Leukemia

by Heleen H. Van Acker, Maarten Versteven, Felix S. Lichtenegger, Gils Roex, Diana Campillo-Davo, Eva Lion, Marion Subklewe, Viggo F. Van Tendeloo, Zwi N. Berneman and Sébastien Anguille

J. Clin. Med. 2019, 8(5), 579; https://doi.org/10.3390/jcm8050579 - 27 Apr 2019

Cited by 40 | Viewed by 7034

Abstract

Acute myeloid leukemia (AML) is a type of blood cancer characterized by the uncontrolled clonal proliferation of myeloid hematopoietic progenitor cells in the bone marrow. The outcome of AML is poor, with five-year overall survival rates of less than 10% for the predominant [...] Read more.

Acute myeloid leukemia (AML) is a type of blood cancer characterized by the uncontrolled clonal proliferation of myeloid hematopoietic progenitor cells in the bone marrow. The outcome of AML is poor, with five-year overall survival rates of less than 10% for the predominant group of patients older than 65 years. One of the main reasons for this poor outcome is that the majority of AML patients will relapse, even after they have attained complete remission by chemotherapy. Chemotherapy, supplemented with allogeneic hematopoietic stem cell transplantation in patients at high risk of relapse, is still the cornerstone of current AML treatment. Both therapies are, however, associated with significant morbidity and mortality. These observations illustrate the need for more effective and less toxic treatment options, especially in elderly AML and have fostered the development of novel immune-based strategies to treat AML. One of these strategies involves the use of a special type of immune cells, the dendritic cells (DCs). As central orchestrators of the immune system, DCs are key to the induction of anti-leukemia immunity. In this review, we provide an update of the clinical experience that has been obtained so far with this form of immunotherapy in patients with AML. Full article

(This article belongs to the Special Issue Immunotherapies for Acute Myeloid Leukemia)

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11 pages, 879 KiB

Open AccessReview

Targeting Immune Signaling Checkpoints in Acute Myeloid Leukemia

by Krzysztof Giannopoulos

J. Clin. Med. 2019, 8(2), 236; https://doi.org/10.3390/jcm8020236 - 12 Feb 2019

Cited by 47 | Viewed by 5046

Abstract

The modest successes of targeted therapies along with the curative effects of allogeneic hematopoietic stem cell transplantation (alloHSCT) in acute myeloid leukemia (AML) stimulate the development of new immunotherapies. One of the promising methods of immunotherapy is the activation of immune response by [...] Read more.

The modest successes of targeted therapies along with the curative effects of allogeneic hematopoietic stem cell transplantation (alloHSCT) in acute myeloid leukemia (AML) stimulate the development of new immunotherapies. One of the promising methods of immunotherapy is the activation of immune response by the targeting of negative control checkpoints. The two best-known inhibitory immune checkpoints are cytotoxic T-lymphocyte antigen-4 (CTLA-4) and the programmed cell death protein 1 receptor (PD-1). In AML, PD-1 expression is observed in T-cell subpopulations, including T regulatory lymphocytes. Increased PD-1 expression on CD8+ T lymphocytes may be one of the factors leading to dysfunction of cytotoxic T cells and inhibition of the immune response during the progressive course of AML. Upregulation of checkpoint molecules was observed after alloHSCT and therapy with hypomethylating agents, pointing to a potential clinical application in these settings. Encouraging results from recent clinical trials (a response rate above 50% in a relapsed setting) justify further clinical use. The most common clinical trials employ two PD-1 inhibitors (nivolumab and pembrolizumab) and two anti-PD-L1 (programmed death-ligand 1) monoclonal antibodies (atezolizumab and durvalumab). Several other inhibitors are under development or in early phases of clinical trials. The results of these clinical trials are awaited with great interest in, as they may allow for the established use of checkpoint inhibitors in the treatment of AML. Full article

(This article belongs to the Special Issue Immunotherapies for Acute Myeloid Leukemia)

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14 pages, 745 KiB

Open AccessReview

Chimeric Antigen Receptor (CAR) T Cell Therapy in Acute Myeloid Leukemia (AML)

by Susanne Hofmann, Maria-Luisa Schubert, Lei Wang, Bailin He, Brigitte Neuber, Peter Dreger, Carsten Müller-Tidow and Michael Schmitt

J. Clin. Med. 2019, 8(2), 200; https://doi.org/10.3390/jcm8020200 - 06 Feb 2019

Cited by 76 | Viewed by 12174

Abstract

Despite high response rates after initial chemotherapy in patients with acute myeloid leukemia (AML), relapses occur frequently, resulting in a five-year-survival by <30% of the patients. Hitherto, allogeneic hemotopoietic stem cell transplantation (allo-HSCT) is the best curative treatment option in intermediate and high [...] Read more.

Despite high response rates after initial chemotherapy in patients with acute myeloid leukemia (AML), relapses occur frequently, resulting in a five-year-survival by <30% of the patients. Hitherto, allogeneic hemotopoietic stem cell transplantation (allo-HSCT) is the best curative treatment option in intermediate and high risk AML. It is the proof-of-concept for T cell-based immunotherapies in AML based on the graft-versus-leukemia (GvL)-effect, but it also bears the risk of graft-versus-host disease. CD19-targeting therapies employing chimeric antigen receptor (CAR) T cells are a breakthrough in cancer therapy. A similar approach for myeloid malignancies is highly desirable. This article gives an overview on the state-of-the art of preclinical and clinical studies on suitable target antigens for CAR T cell therapy in AML patients. Full article

(This article belongs to the Special Issue Immunotherapies for Acute Myeloid Leukemia)

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18 pages, 278 KiB

Open AccessReview

Antigenic Targets for the Immunotherapy of Acute Myeloid Leukaemia

by Ghazala Naz Khan, Kim Orchard and Barbara-ann Guinn

J. Clin. Med. 2019, 8(2), 134; https://doi.org/10.3390/jcm8020134 - 23 Jan 2019

Cited by 6 | Viewed by 3670

Abstract

One of the most promising approaches to preventing relapse is the stimulation of the body’s own immune system to kill residual cancer cells after conventional therapy has destroyed the bulk of the tumour. In acute myeloid leukaemia (AML), the high frequency with which [...] Read more.

One of the most promising approaches to preventing relapse is the stimulation of the body’s own immune system to kill residual cancer cells after conventional therapy has destroyed the bulk of the tumour. In acute myeloid leukaemia (AML), the high frequency with which patients achieve first remission, and the diffuse nature of the disease throughout the periphery, makes immunotherapy particularly appealing following induction and consolidation therapy, using chemotherapy, and where possible stem cell transplantation. Immunotherapy could be used to remove residual disease, including leukaemic stem cells from the farthest recesses of the body, reducing, if not eliminating, the prospect of relapse. The identification of novel antigens that exist at disease presentation and can act as targets for immunotherapy have also proved useful in helping us to gain a better understand of the biology that belies AML. It appears that there is an additional function of leukaemia associated antigens as biomarkers of disease state and survival. Here, we discuss these findings. Full article

(This article belongs to the Special Issue Immunotherapies for Acute Myeloid Leukemia)

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