scholarly journals Emerging Immunotherapy for Acute Myeloid Leukemia

2021 ◽  
Vol 22 (4) ◽  
pp. 1944
Author(s):  
Rikako Tabata ◽  
SungGi Chi ◽  
Junichiro Yuda ◽  
Yosuke Minami
Keyword(s):  
Acute Myeloid Leukemia ◽  
Immune Checkpoint ◽  
Myeloid Leukemia ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Leukemic Cells ◽  
Conventional Chemotherapy ◽  
Relevant Evidence ◽  
Acute Myeloid ◽  
Refractory Aml

Several immune checkpoint molecules and immune targets in leukemic cells have been investigated. Recent studies have suggested the potential clinical benefits of immuno-oncology (IO) therapy against acute myeloid leukemia (AML), especially targeting CD33, CD123, and CLL-1, as well as immune checkpoint inhibitors (e.g., anti-PD (programmed cell death)-1 and anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) antibodies) with or without conventional chemotherapy. Early-phase clinical trials of chimeric antigen receptor (CAR)-T or natural killer (NK) cells for relapsed/refractory AML showed complete remission (CR) or marked reduction of marrow blasts in a few enrolled patients. Bi-/tri-specific antibodies (e.g., bispecific T-cell engager (BiTE) and dual-affinity retargeting (DART)) exhibited 11–67% CR rates with 13–78% risk of cytokine-releasing syndrome (CRS). Conventional chemotherapy in combination with anti-PD-1/anti-CTLA4 antibody for relapsed/refractory AML showed 10–36% CR rates with 7–24 month-long median survival. The current advantages of IO therapy in the field of AML are summarized herein. However, although cancer vaccination should be included in the concept of IO therapy, it is not mentioned in this review because of the paucity of relevant evidence.

scholarly journals Hypomethylating agents in combination with immune checkpoint inhibitors in acute myeloid leukemia and myelodysplastic syndromes

Leukemia ◽  
2018 ◽  
Vol 32 (5) ◽  
pp. 1094-1105 ◽  
Author(s):  
Naval Daver ◽  
Prajwal Boddu ◽  
Guillermo Garcia-Manero ◽  
Shalini Singh Yadav ◽  
Padmanee Sharma ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndromes ◽  
Immune Checkpoint ◽  
Myeloid Leukemia ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Hypomethylating Agents ◽  
Acute Myeloid

scholarly journals Targeting Immune Signaling Checkpoints in Acute Myeloid Leukemia

2019 ◽  
Vol 8 (2) ◽  
pp. 236 ◽  
Author(s):  
Krzysztof Giannopoulos
Keyword(s):  
Immune Response ◽  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Negative Control ◽  
Immune Checkpoints ◽  
Hematopoietic Stem ◽  
Acute Myeloid

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.

scholarly journals Immune-Based Therapeutic Strategies for Acute Myeloid Leukemia

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 105
Author(s):  
Matthias Böhme ◽  
Sabine Kayser
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Myeloid Leukemia ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Solid Cancer ◽  
Drug Conjugates ◽  
Car T ◽  
Immunotherapeutic Strategy ◽  
Acute Myeloid

The development and design of immune-based strategies have become an increasingly important topic during the last few years in acute myeloid leukemia (AML), based on successful immunotherapies in solid cancer. The spectrum ranges from antibody drug conjugates, immune checkpoint inhibitors blocking programmed cell death protein 1 (PD1), cytotoxic T lymphocyte antigen 4 (CTLA4) or T cell immunoglobulin and mucin domain containing-3 (TIM3), to T-cell based monoclonal and bispecific T-cell engager antibodies, chimeric antigen receptor-T-cell (CAR-T) approaches and leukemia vaccines. Currently, there are many substances in development and multiple phase I/II studies are ongoing. These trials will help us to deepen our understanding of the pathogenesis of AML and facilitate the best immunotherapeutic strategy in AML. We discuss here the mode of action of immune-based therapies and provide an overview of the available data.

scholarly journals The Role of T Cell Immunotherapy in Acute Myeloid Leukemia

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3376
Author(s):  
Fang Hao ◽  
Christine Sholy ◽  
Chen Wang ◽  
Min Cao ◽  
Xunlei Kang
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Myeloid Leukemia ◽  
Checkpoint Inhibitors ◽  
Cell Activity ◽  
Leukemic Cells ◽  
Cytotoxic T Cell ◽  
Cell Phenotype ◽  
T Cell Therapy ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a heterogeneous disease associated with various alterations in T cell phenotype and function leading to an abnormal cell population, ultimately leading to immune exhaustion. However, restoration of T cell function allows for the execution of cytotoxic mechanisms against leukemic cells in AML patients. Therefore, long-term disease control, which requires multiple therapeutic approaches, includes those aimed at the re-establishment of cytotoxic T cell activity. AML treatments that harness the power of T lymphocytes against tumor cells have rapidly evolved over the last 3 to 5 years through various stages of preclinical and clinical development. These include tissue-infiltrated lymphocytes (TILs), bispecific antibodies, immune checkpoint inhibitors (ICIs), chimeric antigen receptor T (CAR-T) cell therapy, and tumor-specific T cell receptor gene-transduced T (TCR-T) cells. In this review, these T cell-based immunotherapies and the potential of TILs as a novel antileukemic therapy will be discussed.

scholarly journals Targeting the MTF2-MDM2 Axis Sensitizes Refractory Acute Myeloid Leukemia to Chemotherapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5232-5232
Author(s):  
Hani Jrade ◽  
Harinad B Maganti ◽  
Christopher Cafariello ◽  
Christopher J Porter ◽  
Julien Yockell-Lelièvre ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Risk Groups ◽  
Epigenetic Mechanism ◽  
Leukemic Cells ◽  
Driver Genes ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Acute Myeloid ◽  
Refractory Aml

Abstract Next generation sequencing of acute myeloid leukemia (AML) patient samples has enabled more granular risk stratification of patients; however, refractory AML patients can be found across all risk groups, suggesting that non-genetic lesions regulate chemoresponsiveness. Consistent with this hypothesis is the finding that many of the mutated AML driver genes are encode epigenetic modifiers. Thus, unraveling the epigenetic dysregulation in AML is critical to better understand disease initiation and progression, as well as develop targeted therapies. Metal Response Element Binding Transcription Factor 2/Polycomblike 2 (MTF2/PCL2) plays a fundamental role in recruiting the Polycomb repressive complex 2 (PRC2) to chromatin and we show that it is commonly silenced in primary AML patient cells at diagnosis. Furthermore, the loss of MTF2 in hematopoietic stem and progenitor cells (HSPCs) leads to an altered epigenetic state that underlies refractory AML. By implementing unbiased systems analyses, we identified the E3 ubiquitin ligase MDM2 that inhibits p53 as a direct target of MTF2-PRC2. MTF2 deficiency leads to over-expression of MDM2 and inhibition of p53-mediated cell cycle regulation and apoptosis, leading to chemoresistance and refractory AML. Targeting this dysregulated signaling pathway by MTF2 overexpression or MDM2 inhibitors sensitized refractory patient leukemic cells to induction chemotherapeutics and prevented relapse in AML patient-derived xenograft (PDX) mice. Therefore, we have uncovered a direct epigenetic mechanism by which MTF2 functions as a tumor suppressor required for AML chemotherapeutic sensitivity and identified a potential therapeutic strategy to treat refractory AML. Disclosures Sabloff: Celgene: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Wild-type p53-induced phosphatase sensitizes acute myeloid leukemia cells to conventional chemotherapy

2021 ◽  
Vol 66 (3) ◽  
Author(s):  
Vasily Golotin ◽  
Ekaterina Belotserkovskaya ◽  
Larisa Girshova ◽  
Alexey Petukhov ◽  
Andrey Zaritsky ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Leukemic Cells ◽  
Cell Cycle Distribution ◽  
Wild Type ◽  
Conventional Chemotherapy ◽  
Wild Type P53 ◽  
Acute Myeloid

Recently wild-type p53-induced phosphatase was implicated in the pathogenesis of acute myeloid leukemia (AML) and “pre-leukemia” myeloproliferative conditions. Here we decided to check how the strategy directed to phosphatase inhibition affected sensitivity to conventional chemotherapy. All experiments were conducted on AML cell lines cultivated in vitro. The levels of wild-type p53-induced phosphatase vary in different AML cell lines. The chemical compound GSK2830371 reduced levels of phosphatase and diminished its activity. GSK2830371 did not significantly change the cell cycle distribution of AML cells when used alone or in combination with the anti-cancer chemotherapeutic drug Cytosar but increased caspase-dependent PARP1 cleavage. In contrast with previous studies, we did not observe the negative effect of phosphatase activity inhibition and depletion on cells when a chemical inhibitor was used as monotherapy. Using a combination of GSK2830371 with Cytosar we were able to reduce the threshold of chemotherapy-dependent cytotoxicity and more efficiently eliminate leukemic cells. We propose considering inhibition of wild-type p53-induced phosphatase as a prospective strategy in improving anti-AML therapy.

scholarly journals Acute myeloid leukemia with leukemic pleural effusion and high levels of pleural adenosine deaminase: A case report and review of literature

Open Medicine ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. 387-396
Author(s):  
Sing-Ting Wang ◽  
Chieh-Lung Chen ◽  
Shih-Hsin Liang ◽  
Shih-Peng Yeh ◽  
Wen-Chien Cheng
Keyword(s):  
Acute Myeloid Leukemia ◽  
Pleural Effusion ◽  
Adenosine Deaminase ◽  
Myeloid Leukemia ◽  
Diagnostic Yield ◽  
Leukemic Cells ◽  
Pleural Effusions ◽  
Diagnostic Dilemma ◽  
True Incidence ◽  
Acute Myeloid

Abstract Pleural effusions are rarely observed in association with acute myeloid leukemia (AML), and their true incidence remains unknown. Given the low diagnostic yield from cytopathologic analysis of malignant pleural effusions and the fact that patients with leukemia are often thrombocytopenic and unable to tolerate invasive procedures, the incidence of leukemic effusions may be underestimated. Here, we report a rare case of pleural effusion in a patient with newly diagnosed AML. Initial analysis revealed an exudative, lymphocyte-predominant effusion. High levels of adenosine deaminase (ADA) were detected in pleural fluid, consistent with a diagnosis of tuberculosis. However, the analysis of pleural cytology revealed leukemic cells, permitting the diagnosis of leukemic effusion to be made. The patient underwent induction chemotherapy and pleural effusion resolved without recurrence. This case emphasizes the diagnostic dilemma presented by high levels of ADA in a leukemic pleural effusion, as this association has not been previously considered in the literature.

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