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Cancer Immunology, Immunotherapy : CII Aug 2023Anti-PD-1 monotherapy had limited clinical efficacy in relapsed/refractory (r/r) AML patients with higher PD-1 and PD-L1 expression. Hence, we investigated the efficacy...
Anti-PD-1 monotherapy had limited clinical efficacy in relapsed/refractory (r/r) AML patients with higher PD-1 and PD-L1 expression. Hence, we investigated the efficacy and safety of PD-1 inhibitor with DNA hypomethylating agent (HMA) + CAG regimen in patients who had failed prior AML therapy. In this phase 2, single-arm study, r/r AML patients received azacitidine or decitabine plus CAG regimen with tislelizumab. Primary endpoints were efficacy (objective response rate [ORR]) and safety. Secondary endpoints included overall survival (OS), event-free survival (EFS) and duration of response (DOR). Statistical analyses were performed using Stata 14.0 and SPSS 20.0 software where P < 0.05 denoted significance. Twenty-seven patients were enrolled patients and completed 1 cycle, and 14 (51.9%) and 4 (14.8%) patients completed 2 and 3 cycles, respectively. ORR was 63% (14: complete remission [CR]/CR with incomplete hematologic recovery [CRi], 3: partial remission (PR), 10: no response [NR]). Median OS (mOS) and EFS were 9.7 and 9.2 months, respectively. With a median follow-up of 8.2 months (1.1-26.9), the mOS was not reached in responders (CR/CRi/PR) while it was 2.4 months (0.0-5.4) in nonresponders (P = 0.002). Grade 2-3 immune-related adverse events (irAEs) were observed in 4 (14.8%) patients and 3 nonresponders died of lung infection after treatment. Tislelizumab + HMA + CAG regimen showed improved outcomes in r/r AML patients with lower pretherapy leukemia burden. irAEs were mild and low-grade and higher pretherapy bone marrow CD4 CD127 PD-1 T cells might serve as a predictor of treatment response.ClinicalTrials.gov identifier NCT04541277.
Topics: Humans; Decitabine; Immune Checkpoint Inhibitors; Cytarabine; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols; Leukemia, Myeloid, Acute
PubMed: 37166484
DOI: 10.1007/s00262-023-03454-y -
MBio Oct 2023Epstein-Barr virus (EBV) latency is controlled by epigenetic silencing by DNA methylation [5-methyl cytosine (5mC)], histone modifications, and chromatin looping....
Decitabine disrupts EBV genomic epiallele DNA methylation patterns around CTCF binding sites to increase chromatin accessibility and lytic transcription in gastric cancer.
Epstein-Barr virus (EBV) latency is controlled by epigenetic silencing by DNA methylation [5-methyl cytosine (5mC)], histone modifications, and chromatin looping. However, how they dictate the transcriptional program in EBV-associated gastric cancers remains incompletely understood. EBV-associated gastric cancer displays a 5mC hypermethylated phenotype. A potential treatment for this cancer subtype is the DNA hypomethylating agent, which induces EBV lytic reactivation and targets hypermethylation of the cellular DNA. In this study, we identified a heterogeneous pool of EBV epialleles within two tumor-derived gastric cancer cell lines that are disrupted with a hypomethylating agent. Stochastic DNA methylation patterning at critical regulatory regions may be an underlying mechanism for spontaneous reactivation. Our results highlight the critical role of epigenetic modulation on EBV latency and life cycle, which is maintained through the interaction between 5mC and the host protein CCCTC-binding factor.
Topics: Humans; Chromatin; Herpesvirus 4, Human; CCCTC-Binding Factor; DNA Methylation; Epstein-Barr Virus Infections; Decitabine; Stomach Neoplasms; Virus Latency; DNA; Genomics; Binding Sites
PubMed: 37606370
DOI: 10.1128/mbio.00396-23 -
PloS One 2020We evaluated the outcomes of decitabine as first-line treatment in older patients with acute myeloid leukemia (AML) and investigated the predictors, including a baseline...
PURPOSE
We evaluated the outcomes of decitabine as first-line treatment in older patients with acute myeloid leukemia (AML) and investigated the predictors, including a baseline mini nutritional assessment short form (MNA-SF) score, of response and survival.
PATIENTS AND METHODS
Between 2010 and 2018, 96 AML patients aged 65 and above who received decitabine treatment at 6 centers in Korea were retrospectively evaluated. Response rates, hematologic improvements (HI), progression-free survival (PFS), and overall survival (OS) were analyzed.
RESULTS
The median age at diagnosis was 73.9 years, and the median number of decitabine treatments administered to the patients was 4 (range, 1-29). Of 85 patients, 15 patients (17.6%) achieved complete remission (CR) or CR with incomplete blood count recovery. Twelve patients (14.1%) showed partial remission (PR), and 18 (21.2%) demonstrated HI without an objective response. The median PFS and OS were 7.0 (95% confidence interval [CI], 4.9-9.0) and 10.6 (95% CI, 7.7-13.5%) months, respectively. In multivariate analyses, MNA-SF score ≥ 8 and the absence of peripheral blood (PB) blasts were significant predictors for improved PFS and OS.
CONCLUSIONS
For older patients with newly diagnosed AML, a high MNA-SF score and the absence of PB blasts were independently associated with improved survival.
Topics: Age Factors; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Blood Cell Count; Bone Marrow; Decitabine; Drug Administration Schedule; Female; Humans; Leukemia, Myeloid, Acute; Male; Nutrition Assessment; Progression-Free Survival; Remission Induction; Republic of Korea; Retrospective Studies; Weight Loss
PubMed: 32760083
DOI: 10.1371/journal.pone.0235503 -
Clinical Epigenetics 2018Malignant pleural mesothelioma (MPM) is a very rare and highly aggressive cancer of the pleura associated in most cases with asbestos exposure. To date, no really... (Comparative Study)
Comparative Study
BACKGROUND
Malignant pleural mesothelioma (MPM) is a very rare and highly aggressive cancer of the pleura associated in most cases with asbestos exposure. To date, no really efficient treatments are available for this pathology. Recently, it has been shown that epigenetic drugs, particularly DNA methylation or histone acetylation modulating agents, could be very efficient in terms of cytotoxicity for several types of cancer cells. We previously showed that a hypomethylating agent (decitabine) and a histone deacetylase inhibitor (HDACi) (valproic acid (VPA)) combination was immunogenic and led to the induction of an anti-tumor immune response in a mice model of mesothelioma. However, VPA is not very specific, is active at millimolar concentrations and is responsible for side effects in clinic. To improve this approach, we studied four newly synthetized HDACi, two hydroxamates (ODH and NODH) and two benzamides (ODB and NODB), in comparison with VPA and SAHA. We evaluated their toxicity on immune cells and their immunogenicity on MPM cells in combination with decitabine.
RESULTS
All the tested HDACi were toxic for immune cells at high concentrations. Combination with decitabine increased toxicity of HDACi only towards T-cell clone. A decrease in the proportion of regulatory T cells and natural killer cells was observed in particular with VPA and ODH. In MPM cells, all HDACi combinations induced NY-ESO-1 cancer testis antigen (CTA) expression and the recognition of the treated cells by a NY-ESO-1 specific T-CD8 clone. However, for MAGE-A1, MAGE-A3 and XAGE-1b mRNA expression, the results obtained depended on the HDACi used and on the CTA studied. Depending on the MPM cell line studied, molecules alone increased moderately PD-L1 expression. When combined, a higher stimulation of this immune check point inhibitor expression was observed. Decitabine-induced anti-viral response seemed to be inhibited in the presence of HDACi.
CONCLUSIONS
This work shows that the combination of decitabine and HDACi could be of interest for MPM immunotherapy. However, this combination induced PD-L1 expression which suggests that an association with anti-PD-L1 therapy should be performed to induce an efficient anti-tumor immune response.
Topics: B7-H1 Antigen; Benzamides; Cell Line, Tumor; Cell Proliferation; Cell Survival; DNA Methylation; Decitabine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Immunotherapy; Killer Cells, Natural; Lung Neoplasms; Male; Mesothelioma; Mesothelioma, Malignant; T-Lymphocytes, Regulatory; Valproic Acid; Vorinostat
PubMed: 29946373
DOI: 10.1186/s13148-018-0517-9 -
British Journal of Cancer Feb 2023Decitabine (DAC) is used as the first-line therapy in patients with higher-risk myelodysplastic syndromes (HR-MDS) and elderly acute myeloid leukaemia (AML) patients...
BACKGROUND
Decitabine (DAC) is used as the first-line therapy in patients with higher-risk myelodysplastic syndromes (HR-MDS) and elderly acute myeloid leukaemia (AML) patients unsuitable for intensive chemotherapy. However, the clinical outcomes of patients treated with DAC as a monotherapy are far from satisfactory. Adding all-trans retinoic acid (ATRA) to DAC reportedly benefitted MDS and elderly AML patients. However, the underlying mechanisms remain unclear and need further explorations from laboratory experiments.
METHODS
We used MDS and AML cell lines and primary cells to evaluate the combined effects of DAC and ATRA as well as the underlying mechanisms. We used the MOLM-13-luciferase murine xenograft model to verify the enhanced cytotoxic effect of the drug combination.
RESULTS
The combination treatment reduced the viability of MDS/AML cells in vitro, delayed leukaemia progress, and extended survival in murine xenograft models compared to non- and mono-drug treated models. DAC application as a single agent induced Nrf2 activation and downstream antioxidative response, and restrained reactive oxygen species (ROS) generation, thus leading to DAC resistance. The addition of ATRA blocked Nrf2 activation by activating the RARα-Nrf2 complex, leading to ROS accumulation and ROS-dependent cytotoxicity.
CONCLUSIONS
These results demonstrate that combining DAC and ATRA has potential for the clinical treatment of HR-MDS/AML and merits further exploration.
Topics: Humans; Animals; Mice; Aged; Decitabine; NF-E2-Related Factor 2; Reactive Oxygen Species; Antineoplastic Agents; Myelodysplastic Syndromes; Tretinoin; Leukemia, Myeloid, Acute; Azacitidine
PubMed: 36482192
DOI: 10.1038/s41416-022-02074-0 -
Zhonghua Xue Ye Xue Za Zhi = Zhonghua... Dec 2021To investigate the effects of SPAG6 silencing and decitabine on apoptosis and phosphatase and tensin homolog (PTEN) methylation in SKM-1 cells in vitro and in vivo....
To investigate the effects of SPAG6 silencing and decitabine on apoptosis and phosphatase and tensin homolog (PTEN) methylation in SKM-1 cells in vitro and in vivo. SKM-1 cells were transfected with a lentiviral vector to silence the expression of SPAG6. Cell survival rate was detected by CCK8 after treatment with decitabine, and cell apoptosis was detected by flow cytometry. Protein expression and methylation of PTEN were detected using Western blot and merozoite surface protein (MSP) . An non-obese diabetic/severe combined inmunodeficiency disease (NOD/SCID) mice xenograft tumor model was established, and the apoptosis and PTEN expression of tumor tissue were observed through terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and immunohistochemistry (IHC) , respectively. After lentivirus transfection, SPAG6 in the interference group was silenced successfully. CCK8 results indicated that the cell survival rate of SKM-1 cells treated with decitabine decreased. Flow cytometry showed that the apoptosis rate of cells treated with decitabine [ (17.35±3.37) %] was higher than that of the untreated group (5.09%±2.06%) and the apoptosis rate of the SPAG6 silencing combined with the decitabine treatment group was the highest [ (36.34±4.00) %]. After treatment with decitabine, the expression of DNMT1 decreased, while the expression of PTEN increased, and the promoter methylation degree of PTEN also decreased. Moreover, the increased protein level caused by PTEN demethylation was the most obvious in the SPAG6 in the interference shRNA group treated with decitabine. In NOD/SCID mice, the tumor volume of the decitabine group was significantly smaller than that of the placebo group, and the tumor volume of the SPAG6 silencing combined with the decitabine treatment group was the smallest. Additionally, the apoptosis rate was the highest (the positive ratio was 3.57±0.48) . SPAG6 silencing may enhance the apoptosis level and the effect of PTEN demethylation in SKM-1 cells and enhance the antitumor effect of decitabine in the NOD/SCID xenograft mouse model.
Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Decitabine; Methylation; Mice; Mice, Inbred NOD; Mice, SCID; Microtubule Proteins; Myelodysplastic Syndromes; PTEN Phosphohydrolase; Tensins
PubMed: 35045671
DOI: 10.3760/cma.j.issn.0253-2727.2021.12.007 -
Leukemia Jan 2021Talacotuzumab, a humanized anti-CD123 monoclonal antibody, was evaluated in combination with decitabine in elderly patients with acute myeloid leukemia (AML) not... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety and efficacy of talacotuzumab plus decitabine or decitabine alone in patients with acute myeloid leukemia not eligible for chemotherapy: results from a multicenter, randomized, phase 2/3 study.
Talacotuzumab, a humanized anti-CD123 monoclonal antibody, was evaluated in combination with decitabine in elderly patients with acute myeloid leukemia (AML) not eligible for intensive chemotherapy. A multicenter, phase 2/3 study was initiated to determine the recommended phase 2 dose (RP2D) of talacotuzumab (Part A) followed by an open-label, randomized comparison of talacotuzumab in combination with decitabine versus decitabine alone to assess achievement of complete response (CR) and overall survival (OS) in Part B. Ten patients were enrolled in Part A and 316 in Part B; the results presented here are based on a database lock on January 25, 2018. Part A confirmed the RP2D of talacotuzumab to be 9 mg/kg. In Part B, CR was achieved in 12/80 (15%) patients receiving combination therapy and in 9/82 (11%) patients receiving decitabine alone (odds ratio: 1.4; 95% confidence interval [CI]: 0.6-3.6; p = 0.44). Median (95% CI) OS was 5.36 (4.27-7.95) months for combination therapy versus 7.26 (6.47-8.64) months for decitabine alone (hazard ratio: 1.04; 95% CI: 0.79-1.37; p = 0.78). Combination therapy showed no improvement in efficacy versus decitabine alone, resulting in the Independent Data Monitoring Committee's recommendation of early termination of enrollment and discontinuation of talacotuzumab treatment.
Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Decitabine; Drug Monitoring; Female; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Middle Aged; Prognosis; Research Design; Treatment Outcome
PubMed: 32203138
DOI: 10.1038/s41375-020-0773-5 -
Clinical Epigenetics Jul 2022Several reports have provided crucial evidence in animal models that epigenetic modifications, such as DNA methylation, may be involved in psychostimulant-induced stable...
BACKGROUND
Several reports have provided crucial evidence in animal models that epigenetic modifications, such as DNA methylation, may be involved in psychostimulant-induced stable changes at the cellular level in the brain. Epigenetic editors DNA methyltransferases (DNMTs) and ten-eleven translocation enzymes (TETs) coordinate expression of gene networks, which then manifest as long-term behavioural changes. However, the extent to which aberrant DNA methylation is involved in the mechanisms of substance use disorder in humans is unclear. We previously demonstrated that cocaine modifies gene transcription, via DNA methylation, throughout the brain and in peripheral blood cells in mice.
RESULTS
We treated human peripheral blood mononuclear cells (PBMCs) from healthy male donors (n = 18) in vitro with psychostimulants (amphetamine, cocaine). After treatment, we assessed mRNA levels and enzymatic activities of TETs and DNMTs, conducted genome-wide DNA methylation assays and next-generation sequencing. We found that repeated exposure to psychostimulants decreased mRNA levels and enzymatic activity of TETs and 5-hydroxymethylation levels in PBMCs. These data were in line with observed hyper- and hypomethylation and mRNA expression of marker genes (IL-10, ATP2B4). Additionally, we evaluated whether the effects of cocaine on epigenetic editors (DNMTs and TETs) and cytokines interleukin-6 (IL-6) and IL-10 could be reversed by the DNMT inhibitor decitabine. Indeed, decitabine eliminated cocaine's effect on the activity of TETs and DNMTs and decreased cytokine levels, whereas cocaine increased IL-6 and decreased IL-10.
CONCLUSIONS
Our data suggest that repeated psychostimulant exposure decreases TETs' enzymatic activity in PBMCs. Co-treatment with decitabine reversed TETs' levels and modulated immune response after repeated cocaine exposure. Further investigation is needed to clarify if TET could represent a putative biomarker of psychostimulant use and if DNMT inhibition could have therapeutic potential.
Topics: Animals; Cocaine; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; DNA Modification Methylases; Decitabine; Humans; Interleukin-10; Interleukin-6; Leukocytes, Mononuclear; Male; Mice; RNA, Messenger
PubMed: 35842682
DOI: 10.1186/s13148-022-01303-w -
American Journal of Hematology May 2018
Randomized Controlled Trial
Decitabine improves response rate and prolongs progression-free survival in older patients with newly diagnosed acute myeloid leukemia and with monosomal karyotype: A subgroup analysis of the DACO-016 trial.
Topics: Aged; Aged, 80 and over; Decitabine; Humans; Karyotyping; Leukemia, Myeloid, Acute; Monosomy; Progression-Free Survival; Survival Analysis
PubMed: 29417613
DOI: 10.1002/ajh.25062 -
Medicine Jun 2020Resistance to targeted and immune checkpoint blockade treatment remains a major problem in patients with advanced metastatic melanoma. To overcome this problem, there...
INTRODUCTION
Resistance to targeted and immune checkpoint blockade treatment remains a major problem in patients with advanced metastatic melanoma. To overcome this problem, there needs to be a decrease in burden of disease as well as re-establishing of immune sensitivity. The aim of this early phase 2 clinical trial is to investigate a novel way of sequencing and combining decitabine and carboplatin to decrease methylation and increase DNA repair resulting in a decrease in the disease burden and to re-establish sensitivity to the immune response.
METHODS AND ANALYSIS
This single-site early phase 2 clinical trial will be conducted in 30 patients with metastatic melanoma that are resistant to all approved therapies. Patients will receive 2 × 4-week cycles of decitabine 7 mg/m IVI/day for 5 days (D1-D5) followed by Carboplatin AUC 5 IVI on D8; Week 3 and Week 4 no treatment. The primary objective is to determine DNA methylation and DNA repair levels before, and immediately after treatment; quantify immune-response markers (PDL-1, PD-1, CD4/CD8, and CD68) in blood, tumor and microenvironment before treatment and after 2 cycles. The secondary outcome objective is to quantify response rate (RR) to administration of 2 cycles of decitabine and carboplatin cycle using response evaluation criteria in solid tumors (RECIST 1.1) criteria. This data will be used to calculate sample size and determine statistical analysis plan for larger Phase 2 study.
ETHICS AND DISSEMINATION
Protocol version 1.1 was reviewed and approved by the Hunter New England Health Human Research Ethics Committee (Reference No: 15/12/16/3.08, NSW HREC Reference No: HREC/15/HNE/505) and site-specific approval from the Calvary Mater Hospital Newcastle, NSW, Australia (NSW SSA Reference No: SSA/16/HNE/224). Primary and secondary outcomes and safety data will be disseminated through publications.
TRIAL REGISTRATION DETAILS
Australian New Zealand Clinical Trial Registry ACTRN12616000440426.
Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Clinical Trials, Phase II as Topic; Decitabine; Humans; Melanoma; Pilot Projects
PubMed: 32569203
DOI: 10.1097/MD.0000000000020705