scholarly journals Multifunctional nanoparticle-mediated SHARP1 knockdown in MLL-AF6 acute myeloid leukemia

2021 ◽  
Author(s):  
Sameh A. Mohammed ◽  
Yang Ju
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
State Of The Art ◽  
Therapeutic Option ◽  
Protein Accumulation ◽  
Antileukemic Activity ◽  
Multifunctional Nanoparticle ◽  
Liposomal Nanoparticles ◽  
Interfering Rna ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) has an extremely poor prognosis and high relapse and fatality rates. We targeted SHARP1 using multifunctional small interfering RNA (siRNA) and bortezomib (BTZ)-loaded cRGD-guided PEGylated cationic liposomal nanoparticles to monitor their antileukemic activity in MLL-AF6 AML cells. Efficient siRNA/BTZ co-delivery by the nanoparticles significantly inhibited cell viability, decreasing clonogenic growth of AML cells and stimulating robust apoptosis. We hypothesized that SHARP1 downregulation induced nonfunctional MLL-AF6, DOT1L, MEN1, and LEDGF fusion protein accumulation, preventing MLL-AF complex formation and downregulating RAS-GTP and Bcl-2, consequently triggering autophagy and apoptosis. The BTZ combination substantially augmented therapeutic synergy leading to enhanced autophagic and apoptotic events. Our findings demonstrate a state-of-the-art biodegradable nanoplatform for siRNA/BTZ co-delivery with targeted SHARP1 knockdown, demonstrating a potential therapeutic option for MLL-AF6 AML.

scholarly journals Dissecting the Immune Landscape of Acute Myeloid Leukemia

Biomedicines ◽  
2018 ◽  
Vol 6 (4) ◽  
pp. 110 ◽  
Author(s):  
Jan Davidson-Moncada ◽  
Elena Viboch ◽  
Sarah Church ◽  
Sarah Warren ◽  
Sergio Rutella
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Clinical Success ◽  
Therapeutic Option ◽  
Immune Checkpoint Blockade ◽  
Response To Treatment ◽  
Variable Response ◽  
Molecular Features ◽  
Therapeutic Decisions ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a molecularly heterogeneous hematological malignancy with variable response to treatment. Recurring cytogenetic abnormalities and molecular lesions identify AML patient subgroups with different survival probabilities; however, 50–70% of AML cases harbor either normal or risk-indeterminate karyotypes. The discovery of better biomarkers of clinical success and failure is therefore necessary to inform tailored therapeutic decisions. Harnessing the immune system against cancer with programmed death-1 (PD-1)-directed immune checkpoint blockade (ICB) and other immunotherapy agents is an effective therapeutic option for several advanced malignancies. However, durable responses have been observed in only a minority of patients, highlighting the need to gain insights into the molecular features that predict response and to also develop more effective and rational combination therapies that address mechanisms of immune evasion and resistance. We will review the state of knowledge of the immune landscape of AML and identify the broad opportunity to further explore this incompletely characterized space. Multiplexed, spatially-resolved immunohistochemistry, flow cytometry/mass cytometry, proteomic and transcriptomic approaches are advancing our understanding of the complexity of AML-immune interactions and are expected to support the design and expedite the delivery of personalized immunotherapy clinical trials.

scholarly journals High-dose cytosine arabinoside and mitoxantrone: a highly effective regimen in refractory acute myeloid leukemia

Blood ◽  
1987 ◽  
Vol 69 (3) ◽  
pp. 744-749 ◽  
Author(s):  
W Hiddemann ◽  
H Kreutzmann ◽  
K Straif ◽  
WD Ludwig ◽  
R Mertelsmann ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Cytosine Arabinoside ◽  
Myeloid Leukemia ◽  
High Dose ◽  
Antileukemic Activity ◽  
First Line ◽  
Clinical Phase ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid

Abstract In a clinical phase I/II study, high-dose cytosine arabinoside and mitoxantrone (HAM) were given in combination to 40 patients with refractory acute myeloid leukemia. All patients had received a 9-day combination of thioguanine, Ara-C, and daunorubicin (TAD-9) as standardized first-line treatment. Refractoriness was defined as (a) nonresponse against two TAD-9 induction cycles, (b) early relapse within the first 6 months on monthly maintenance or after TAD-9 consolidation, (c) relapse after 6 months with nonresponse against one additional TAD-9 cycle, and (d) second and subsequent relapses after successful TAD-9 therapy at the preceding relapse. Therapy consisted of HD-Ara-C 3 g/m2 every 12 hours on days 1 through 4; mitoxantrone was started at 12 mg/m2/day on days 3, 4, and 5 and was escalated to 4 and 5 doses of 10 mg/m2/day on days 2 through 5 and 2 through 6. Of the 40 patients, 21 achieved a complete remission (53%), 1 patient had a partial remission, and 5 patients were nonresponders. Thirteen patients died in aplasia due to infections (n = 11), pericardiac effusion, or acute cardiomyopathy. Nonhematologic side effects consisted predominantly of nausea and vomiting, mucositis, and diarrhea. Central nervous system (CNS) symptoms were observed during six treatment courses. Recovery of blood counts occurred at a median of 27 days from the onset of treatment; the median time to complete remission was 36 days. Two of the 21 responders underwent successful bone marrow transplantations. The median remission duration for the remaining 19 patients is 4.5 months, and the median survival time is 9 months. These data emphasize that HAM has high antileukemic activity in refractory AML and strongly suggest starting the combination at earlier stages in AML therapy.

scholarly journals Antigen-specific immunotherapies for acute myeloid leukemia

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 584-595 ◽  
Author(s):  
Sarah A. Buckley ◽  
Roland B. Walter
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Gemtuzumab Ozogamicin ◽  
Treatment Modalities ◽  
Target Antigen ◽  
Antileukemic Activity ◽  
Care Needs ◽  
Antibody Drug Conjugate ◽  
Acute Myeloid

Abstract Antigen-specific immunotherapies have emerged as important components of curative treatment algorithms for many cancers. In acute myeloid leukemia (AML), success has been less obvious. Nonetheless, among the few drugs shown to improve survival in recent randomized trials is the CD33 antibody–drug conjugate gemtuzumab ozogamicin. Significant antileukemic activity is also well documented for radioimmunoconjugates targeting CD33, CD45, or CD66. These therapeutics can intensify conditioning before hematopoietic cell transplantation, but their effect on patient outcomes needs clarification. Emerging data now suggest clinical antileukemic activity of several novel antibodies and perhaps some adoptive T-cell immunotherapies and vaccines. In parallel, numerous other agents targeting a wider variety of antigens are currently being explored. However, the antigenic heterogeneity characteristic of AML is a considerable limitation for all these therapeutics, and many important questions related to the ideal target antigen(s), disease situation in which to use these therapies, most suitable patient populations, exact treatment modalities, and details of supportive care needs remain open. Addressing such questions in upcoming studies will be required to ensure that antigen-directed therapies become an effective tool in AML, a disease for which outcomes with standard “3 + 7”-based chemotherapy have remained unsatisfactory in many patients.

Immunogenicity and Antileukemic Activity of Dendritic Cells Electroporated with Wilms’ Tumor WT1 mRNA: A Phase I/II Trial in Acute Myeloid Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 830-830 ◽  
Author(s):  
Zwi N. Berneman ◽  
Ann Van de Velde ◽  
Ann Van Driessche ◽  
Nathalie Cools ◽  
Barbara Stein ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Wilms Tumor ◽  
Rna Expression ◽  
Antileukemic Activity ◽  
Dc Vaccines ◽  
Acute Myeloid

Abstract The Wilms’ tumor protein WT1 is a target for immunotherapy in malignancies, such as acute myeloid leukemia (AML). Following our demonstration that dendritic cells (DC) can be efficiently transfected by messenger (m)RNA electroporation (Van Tendeloo VF et al. Blood2001;98:49–56) and that WT1 mRNA-electroporated DC stimulate WT1-specific T cells in vitro (Van Driessche A et al. Leukemia2005;19:1863–1871), we performed a phase I/II dose-escalation trial, in which patients with AML in remission but at high risk of relapse and without a direct sib allo-transplant option (9 patients) or with slowly progressive AML (1 patient) received intradermal injections of WT1 RNA-loaded DC. Following apheresis and CD14 immunomagnetic monocyte separation, DC were generated in 6-day cultures in clinical-grade medium supplemented with serum, granulocytemacrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4, matured with prostaglandin (PG)E2 and tumor necrosis factor (TNF)-alpha, harvested, electroporated with WT1 mRNA and used as vaccines. The patients received four biweekly DC vaccines and a delayed-type hypersensitivity (DTH) test was performed 2 weeks following the last vaccination. Patients were monitored for minimal residual disease (MRD) by analyzing WT1 RNA expression in peripheral blood by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) (Cilloni D et al. Leukemia2002;16:2115–2121 & Cilloni D et al. Haematologica2008;93:921–924). Before and after vaccination, peripheral blood was collected for immunomonitoring purposes. Feasibility, safety, immunogenicity and effect on MRD were investigated. There was successful DC generation and vaccine production in all 10 patients. No serious adverse events or toxicity were observed and vaccinations were well tolerated. A decrease in WT1 RNA expression was observed during the course of the vaccination in 4/7 patients who had an increased WT1 mRNA level in peripheral blood. Three of those patients are still in complete hematological remission. An in vivo vaccine-specific immune response was demonstrated in 10/10 patients by DTH. Ex vivo immunomonitoring analysis showed a significant increase in circulating activated HLA-DR+ CD4+ T cells and in IL-2 plasma levels following vaccination. Importantly, in vitro restimulation assays of peripheral blood mononuclear cells revealed a significant postvaccination increase in interferon (IFN)-gamma-producing WT1-specific CD8+ T cells (n= 8 evaluable patients), but not in cytokine-producing WT1-specific CD4+ T cells. There was no significant change in WT1-specific antibodies following vaccination. We conclude that vaccination of AML patients with WT1 RNA-loaded DC is feasible and safe. Furthermore, the DC elicit vaccine-specific and WT1-specific CD8+ T-cell responses. The correlation between reduction of circulating WT1 mRNA and the administration of the DC vaccines strongly suggests that this DC vaccine elicits an antileukemic activity.

Clinical and immune responses of WT1-peptide vaccination in patients with acute myeloid leukemia

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2511-2511 ◽  
Author(s):  
U. Keilholz ◽  
A. Letsch ◽  
A. Asemissen ◽  
W. Hofmann ◽  
L. Uharek ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
High Risk ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Wilms Tumor ◽  
Intracellular Cytokine Staining ◽  
T Cell Response ◽  
Antileukemic Activity ◽  
Acute Myeloid

2511 Background: The transcription factor Wilms tumor protein (WT) 1 belongs to a new generation of tumor antigens, as it is essential for tumor cell proliferation. WT1 is highly expressed both in myeloid leukemias and many carcinomas. This phase 2 proof-of-concept trial was initiated to determine immunogenicity and toxicity of vaccination with a novel HLA-A2-restricted WT1 peptide vaccine. Methods: Sixteen HLA-A2-positive patients with acute myeloid leukemia and one patient with myelodysplasia received 3–18 vaccinations (median 8) of WT1. 126–134 peptide (0.2 mg) together with the T helper protein keyhole limpet hemocyanin (1 mg) and in addition GM-CSF (75 mcg for four days) and. Twelve patients had elevated blast counts at study entry and 5 patients complete remission with high risk for relapse. Results: Six of 12 patients with presence of leukemic blasts had evidence of antileukemic activity. One patient achieved complete remission for 12 months. The patient with myelodysplasia RAEB II had a major response of neutrophils and platelets. Two patients had minor responses with transient clearance of peripheral blasts or improvement of hematopoiesis, and two patients achieved disease stabilization for 3 and 14 months. WT1 transcripts as molecular disease marker decreased in 5 of these 6 patients and also in 4 of 5 high-risk patients. No significant toxicity occurred. The generation of a WT1-specific T cell response in peripheral blood and bone marrow was detected in 9 of 13 patients by tetramer analysis and 8 of 13 patients by intracellular cytokine staining. Conclusion: These results show that WT1 vaccination can induce functional T cell responses associated with antileukemic activity and warrant trials of WT1 vaccination in patients at high risk of relapse and with WT1-expressing carcinomas. No significant financial relationships to disclose.

scholarly journals Azelaic Acid Exerts Antileukemic Activity in Acute Myeloid Leukemia

2017 ◽  
Vol 8 ◽  
Author(s):  
Yunbao Pan ◽  
Dong Liu ◽  
Yongchang Wei ◽  
Dan Su ◽  
Chenyang Lu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Azelaic Acid ◽  
Myeloid Leukemia ◽  
Antileukemic Activity ◽  
Acute Myeloid
Sign in / Sign up

Export Citation Format

Share Document