scholarly journals Will deeper characterization of the landscape of immune checkpoint molecules in acute myeloid leukemia bone marrow lead to improved therapeutic targeting?

Cancer ◽  
2019 ◽  
Vol 125 (9) ◽  
pp. 1410-1413 ◽  
Author(s):  
Esten N. Vandsemb ◽  
Tae Kon Kim ◽  
Amer M. Zeidan
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Immune Checkpoint ◽  
Myeloid Leukemia ◽  
Therapeutic Targeting ◽  
Immune Checkpoint Molecules ◽  
Acute Myeloid

scholarly journals Expression of immune checkpoint molecules in Iraqi acute myeloid leukemia patients

2021 ◽  
Vol 10 (1) ◽  
pp. 1
Author(s):  
HassnienSamir Al-Hashemi ◽  
SabahA. Hameid A. Rahman ◽  
ZeyadAhmed Shabeeb
Keyword(s):  
Acute Myeloid Leukemia ◽  
Immune Checkpoint ◽  
Myeloid Leukemia ◽  
Immune Checkpoint Molecules ◽  
Acute Myeloid

scholarly journals Epigenetic Silencing of Immune-Checkpoint Receptors in Bone Marrow- Infiltrating T Cells in Acute Myeloid Leukemia

2021 ◽  
Vol 11 ◽  
Author(s):  
Ramin Radpour ◽  
Miriam Stucki ◽  
Carsten Riether ◽  
Adrian F. Ochsenbein
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Histone Deacetylase ◽  
Immune Checkpoint ◽  
Myeloid Leukemia ◽  
Expression Profiles ◽  
Epigenetic Silencing ◽  
Acute Myeloid

BackgroundImmune-checkpoint (IC) inhibitors have revolutionized the treatment of multiple solid tumors and defined lymphomas, but they are largely ineffective in acute myeloid leukemia (AML). The reason why especially PD1/PD-L1 blocking agents are not efficacious is not well-understood but it may be due to the contribution of different IC ligand/receptor interactions that determine the function of T cells in AML.MethodsTo analyze the interactions of IC ligands and receptors in AML, we performed a comprehensive transcriptomic analysis of FACS-purified leukemia stem/progenitor cells and paired bone marrow (BM)-infiltrating CD4+ and CD8+ T cells from 30 patients with AML. The gene expression profiles of activating and inhibiting IC ligands and receptors were correlated with the clinical data. Epigenetic mechanisms were studied by inhibiting the histone deacetylase with valproic acid or by gene silencing of PAC1.ResultsWe observed that IC ligands and receptors were mainly upregulated in leukemia stem cells. The gene expression of activating IC ligands and receptors correlated with improved prognosis and vice versa. In contrast, the majority of IC receptor genes were downregulated in BM-infiltrating CD8+ T cells and partially in CD4+ T cells, due to pathological chromatin remodeling via histone deacetylation. Therefore, treatment with histone deacetylase inhibitor (HDACi) or silencing of PAC1, as a T cell-specific epigenetic modulator, significantly increased the expression of IC receptors and defined effector molecules in CD8+ T cells.ConclusionsOur results suggest that CD8+ T cells in AML are dysfunctional mainly due to pathological epigenetic silencing of activating IC receptors rather than due to signaling by immune inhibitory IC receptors, which may explain the limited efficacy of antibodies that block immune-inhibitory ICs in AML.

Characterization of bone marrow mast cells in acute myeloid leukemia with t(8;21) (q22;q22); RUNX1-RUNX1T1

2013 ◽  
Vol 37 (11) ◽  
pp. 1572-1575 ◽  
Author(s):  
Sheeja T. Pullarkat ◽  
Vinod Pullarkat ◽  
Anand Lagoo ◽  
Russell Brynes ◽  
Lawrence M. Weiss ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Mast Cells ◽  
Myeloid Leukemia ◽  
Acute Myeloid

scholarly journals Phenotypic Characterization of the Immune Landscape in the Bone Marrow of Patients with Acute Myeloid Leukemia (AML) Using MultiOmyxTM Hyperplexed Immunofluorescence Assay

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1455-1455
Author(s):  
Qingyan Au ◽  
Arezoo Hanifi ◽  
Erinn Parnell ◽  
Judy Kuo ◽  
Eric Leones ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Immune Cells ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Phenotypic Characterization ◽  
M2 Macrophages ◽  
Essential Information ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML) is a clinically and molecularly heterogeneous disorder. Bone marrow (BM) constitutes the home niche for leukemia cells in AML. Emerging data indicates that the BM microenvironment becomes immunosuppressive and plays a crucial role in cancer development and progression. Regulatory T cells (Treg), tumor associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) all contribute to immunologically permissive microenvironment for cancer cells. Based on phenotypical characteristics, MDSC can be further subdivided into granulocytic MDSC (G-MDSC, polymorphonuclear MDSC) and monocytic MDSC (M-MDSC). Although increasing evidence suggests that the immune system impacts the pathogenesis and prognosis in AML patients, only limited data has been published to comprehensively describe the immunological composition of AML BM microenvironment. Methods: In this study, we aimed to perform comprehensive characterization of the immune cells in the BM of patients with AML. Using MultiOmyx hyperplexed immunofluorescence (IF) assay and proprietary imaging analysis, we studied BM tissues of 20 AML patients and 6 normal controls with a total of 13 markers essential in cancer immunology. The normal and AML BM FFPE sections were stained with CD34, Arginase1, CD11b, CD14, CD15, CD33, CD68, CD163, HLA-DR, CD3, CD4, CD8 and FOXP3. Results: Overall, MultiOmyx 13-plex panel staining results revealed an immune suppression-skewed immune profile in AML BM in this study. We observed that both M-MDSC and G-MDSC accumulated within the TME in AML BM samples, with higher frequency of G-MDSCs over M- MDSCs. The data also revealed an abundant M2 macrophages present in the TME of the AML samples. The detection of both MDSCs and M2 macrophages in these samples supports the hypothesis that these cells contribute to the establishment of an immunosuppressive TME. Using the MultiOmyx proprietary algorithm, which takes into account the staining patterns, we quantified the counts and density of different immune cells in both AML patient and normal BM samples. There was a significantly higher frequency of M2 TAM in AML than normal BM. Increased M-MDSC to G-MDSC ratio was also noted in patients with AML. Further, the spatial distance from the different subsets of immunosuppressive cells to CD34+ blasts was measured in AML samples using nearest neighbor analysis. The data indicated that G-MDSC were spatially closer to CD34+ blasts in AML than M-MDSC. Conclusions: The direct assessment of immune phenotypes and their spatial relationship by MultiOmyx IF assay provides essential information in understanding the immune landscape in AML BM. Together, our data suggests that AML blasts may directly recruit immunosuppressive Tregs, MDSC and TAM and this may be one of the escape strategies. The potential for eradicating AML lies in rational combinations of immunotherapies with strategies of the induction of anti-tumor immunity and the elimination or reprogramming of the immunosuppressive TME. Disclosures No relevant conflicts of interest to declare.

Enasidenib: First Mutant IDH2 Inhibitor for the Treatment of Refractory and Relapsed Acute Myeloid Leukemia

2019 ◽  
Vol 18 (14) ◽  
pp. 1936-1951 ◽  
Author(s):  
Raghav Dogra ◽  
Rohit Bhatia ◽  
Ravi Shankar ◽  
Parveen Bansal ◽  
Ravindra K. Rawal
Keyword(s):  
Clinical Trial ◽  
Bone Marrow ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Adverse Effects ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
White Blood Cells ◽  
Phase Iii ◽  
Acute Myeloid

Background: Acute myeloid leukemia is the collective name for different types of leukemias of myeloid origin affecting blood and bone marrow. The overproduction of immature myeloblasts (white blood cells) is the characteristic feature of AML, thus flooding the bone marrow and reducing its capacity to produce normal blood cells. USFDA on August 1, 2017, approved a drug named Enasidenib formerly known as AG-221 which is being marketed under the name Idhifa to treat R/R AML with IDH2 mutation. The present review depicts the broad profile of enasidenib including various aspects of chemistry, preclinical, clinical studies, pharmacokinetics, mode of action and toxicity studies. Methods: Various reports and research articles have been referred to summarize different aspects related to chemistry and pharmacokinetics of enasidenib. Clinical data was collected from various recently published clinical reports including clinical trial outcomes. Result: The various findings of enasidenib revealed that it has been designed to allosterically inhibit mutated IDH2 to treat R/R AML patients. It has also presented good safety and efficacy profile along with 9.3 months overall survival rates of patients in which disease has relapsed. The drug is still under study either in combination or solely to treat hematological malignancies. Molecular modeling studies revealed that enasidenib binds to its target through hydrophobic interaction and hydrogen bonding inside the binding pocket. Enasidenib is found to be associated with certain adverse effects like elevated bilirubin level, diarrhea, differentiation syndrome, decreased potassium and calcium levels, etc. Conclusion: Enasidenib or AG-221was introduced by FDA as an anticancer agent which was developed as a first in class, a selective allosteric inhibitor of the tumor target i.e. IDH2 for Relapsed or Refractory AML. Phase 1/2 clinical trial of Enasidenib resulted in the overall survival rate of 40.3% with CR of 19.3%. Phase III trial on the Enasidenib is still under process along with another trial to test its potency against other cell lines. Edasidenib is associated with certain adverse effects, which can be reduced by investigators by designing its newer derivatives on the basis of SAR studies. Hence, it may come in the light as a potent lead entity for anticancer treatment in the coming years.

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