Role Of Decitabine Research Articles

A Novel Cognition of Decitabine: Insights into Immunomodulation and Antiviral Effects.

DNA methylation, as one of the major means of epigenesis change, makes a large difference in the spatial structure of chromatin, transposable element activity and, fundamentally, gene transcription. It has been confirmed that DNA methylation is closely related to innate immune responses. Decitabine, the most efficient available DNA methyltransferase inhibitor, has demonstrated exhilarating immune activation and antiviral effects on multiple viruses, including HIV, HBV, HCV, HPV and EHV1. This review considers the role of decitabine in regulating innate immune responses and antiviral ability. Understanding the complex transcriptional and immune regulation of decitabine could help to identify and validate therapeutic methods to reduce pathogen infection-associated morbidity, especially virus infection-induced morbidity and mortality.

Decitabine: A Historical Review of the Development Process of an Epigenetic Drug

Decitabine (5-aza-2p-deoxycytidine) is a hypomethylation agent with a double-action mechanism, these are the reactivation of silenced genes; exhibiting differentiation at low doses and showing cytotoxicity at high doses. Decitabine was used as a classic anticancer drug in the original studies in the 1980s, 1500 to 2500 mg/m2 per cycle was the maximum clinically tolerated dose. The dosage was reassessed after a better understanding of epigenetics in cancer and the role of decitabine in epigenetic (hypomethylation) therapy was obtained, in about 1/20th of the previous doses (i.e., 'optimal biological' doses modulating hypomethylation). It has been found that decitabine (100 to 150 mg / m2 per cycle) can be used in patients with myelodysplastic syndromes (MDS) and other myeloid tumors, with manageable side effects. Combination therapies that amplify the epigenetic effect of decitabine will most likely improve the patient responses and allow it to be used in the treatment of other malignancies.

IMMU-50. SYSTEMIC ADOPTIVE TRANSFER IMMUNOTHERAPY WITH TCR-TRANSDUCED T-CELLS TARGETING NY-ESO-1 FOR MENINGIOMA

Abstract INTRODUCTION The lack of immunotherapeutic antigen targets selectively expressed on meningiomas have historically hindered its immunotherapy development. However, recent literature showed that in meningiomas, NY-ESO-1 is the most frequently expressed Cancer-Testis(CT)-antigen, which is a group of proteins silent in somatic cells but reactivated in cancers. NY-ESO-1 also has higher expression in higher-grade meningiomas. Decitabine is known to upregulate CT-antigens and augment immunotherapy. To evaluate systemic adoptive transfer for meningiomas, we tested the efficacy of NY-ESO-1 T-cell-receptor(TCR)-transduced T-cells in vitro and in vivo, and the role of decitabine in meningioma immunotherapy. METHODS NY-ESO-1 TCR-Transduced T-cells were generated by double-transfection with supernatants from PG-13 retroviral packaging cell line encoding HLA-A*0201–restricted NY-ESO-1(157 – 165)-specific TCR. In vitro cytolysis was measured using the xCelligence Real-Time Cell Analyzer System. We utilized human meningioma cells SF1335(Grade I, HLA-A2.1 positive) and CH157(Grade III, HLA-A2.1 negative) in vitro and in vivo. RESULTS CH157 and SF1335 have high and low NY-ESO-1 expression, respectively. Decitabine upregulated NY-ESO-1 mRNA expression in SF1335 by 6-fold after 2 days and by 100-fold after 9 days, with similar effect on protein expression. Co-culturing CH157, CH157-HLA-A2.1(CH157 transduced with HLA-A2.1 vector), SF1335, and decitabine-pretreated-SF1335 cells individually with NY-ESO-1 TCR transduced T-cells at a ratio of 1:1 resulted in 0%, 65%, 20% and 40% cytolysis at 10hours, respectively. Systemic(intravenous) adoptive transfer of TCR-transduced T-cells significantly increased overall survival in NSG mice with intracranial xenografts of CH157-HLA-A2.1 (p=0.04) and SF1335(not treated with decitabine) (p=0.06). CONCLUSIONS NY-ESO-1 TCR-transduced T-cells induce NY-ESO-1 and HLA-A2.1-specific cytolysis in meningioma in vitro, and systemic adoptive transfer confers a statistically significant survival benefit in vivo for meningiomas with high NY-ESO-1 expression. Decitabine upregulates NY-ESO-1 expression and increases tumor cytolysis by TCR-transduced T-cells in meningiomas. Targeting NY-ESO-1 may be a clinically feasible immunotherapeutic strategy to treat aggressive meningiomas.

Abstract PR12: Epigenetic reprograming promotes an immunogenic ovarian tumor microenvironment and synergizes with adoptive transfer of engineered T cells expressing NY-ESO-1 specific T cell receptors

Abstract The ability of the immune system to recognize and reject tumors is dependent on several factors that include the expression of immunogenic target antigens on tumor cells, generation of high frequencies of tumor antigen-specific T cells with potent effector function, and capacity to overcome several mechanisms by which tumors escape immune attack. The immunosuppressive environment in the tumor bearing host and at the tumor site restricts persistence and function of antigen-specific T cells, and represent a major obstacle to a durable adoptive engineered TCR (T-cell receptor) cell transfer immunotherapy. DNA demethylation agents have been shown to change immune gene signatures of tumor cells and activate the expression of suppressed tumor antigens by relieving promotor hyper-methylation. In the current study, we aim to determine the immunomodulatory activity of demethylation agents on both ovarian cancer cells and immune cell components in tumor microenvironment, and identify strategies to enhance adoptive T-cell transfer (ACT) immunotherapy in ovarian cancer models. Using a preclinical xenograft model, NY-ESO-1 negative ovarian cancer, OVCAR3, we investigated therapeutic effects of three HLA-A*02 restricted clones of NY-ESO-1 specific CD8 TCR gene-engineered T cells in combination with the demethylation agents decitabine and SGI-110. Demethylation agent treatment followed by ACT elicited synergistic antitumor responses, ranging from inhibition to regression of tumor growth, with curative effect in some animals. In the NY-ESO-1 negative OVCAR3 model, demethylation agents not only induced expression of NY-ESO-1 tumor antigen and MHC I and II, rendering the tumor visible for recognition by CD8 T cells, but also dramatically promoted persistence and accumulation of adoptively transferred T cells at tumor site, as well as reduction of suppressive myeloid cells in the tumor. To further optimize the therapeutic effect of NY-ESO-1 specific CD8 T cells, we explored the activity of TCR gene-engineered NY-ESO-1 specific CD4 T cells that directly recognize cancer cells in a MHC II-restricted manner, in combination with decitabine. We also demonstrated that decitabine rendered the tumor visible for recognition by NY-ESO-1 specific CD4 T cells leading to significant tumor inhibition, and improved persistency of CD4 T cells at peripheral and tumor sites. To maximize curative effect and durability of the therapy, we are currently investigating the immunomodulatory role of decitabine in combination with both CD8 and CD4 T cells specific to NY-ESO-1 in ovarian cancer. Our findings provide insights into novel modes of action of demethylation agents, and indicate that, with optimized therapeutic strategies, demethylation agents can dramatically augment efficacy of adoptive T-cell transfer immunotherapy and counter the immunosuppressive mechanisms in ovarian cancer models. This abstract is also being presented as Poster B34. Citation Format: Li Shen, Bob McGray, Anthony Miliotto, Ariel Francois, Cheryl Eppolito, Junko Matsuzaki, Takemasa Tsuji, Richard Koya, Adekunle Odunsi. Epigenetic reprograming promotes an immunogenic ovarian tumor microenvironment and synergizes with adoptive transfer of engineered T cells expressing NY-ESO-1 specific T cell receptors. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr PR12.

Research progress of decitabine in myelodysplastic syndromes

It provides a new approach to treat myelodysplastic syndromes when decitabine comes out. In order to improve the understanding of the role of decitabine and to provide a reference for the clinical treatment of middle-risk and high-risk myelodysplastic syndromes, this article mianly summarized drug combination, prognostic molecular markers, and reviewed the mechanism of action, main medication regimen in recent 5 years for the treatment of middle-risk and high-risk myelodysplastic syndromes with decitabine. Key words: Deoxycholic acid/AA/TU; Myelodysplastic syndromes/DT; Review

Decitabine treatment of extramedullary relapse in one patient with T-ALL transformed from myelodysplastic syndrome after allo-PBSCT

Objective: To report the critical role of decitabine in treatment of a patient with T cell acute lymphoblastic leukemia (T-ALL) transformed from myelodysplastic syndrome (MDS) post-transplantation.Methods: This patient initially displayed MDS-refractory cytopenia with multilineage dysplasia (RCMD) with a chimeric chromosome of trisomy 8 and normal karyotype. Two years later, he had progressed to T-ALL, his karyotype had completely transformed to trisomy 8. Six months after a matched-related allogeneic peripheral blood stem cell transplantation (allo-PBSCT), he presented with a tumor measuring 5.5 × 3.9 × 7.1 cm in front of the mediastinum that was metabolically active (SUVmax 6.6), assessed using position emission tomography–CT (PET–CT). Tumor immunostaining was positive for CD3, TdT, CD99, CD4, CD8 and Ki67, suggestive of T cell lymphoblastic lymphoma. One month after immunosuppression had been discontinued, the tumor size decreased to 4.0 × 3.3 × 5.5 cm with a reduction in metabolic activity to 3.0 (SUVmax). Subsequently, he was treated with cyclosporine A and prednisone against chronic graft versus host disease. He was then treated with decitabine alone (20 mg/m2/d, 5 days/month) for 4 months without serious side effects.Results: Thus far, his bone marrow has remained in complete remission. PET–CT scan revealed a decrease in tumor size to 2.6 × 1.9 × 3.3 cm and a reduction in metabolic activity to 1.5 (SUVmax) without the detection of current disease during therapy.Conclusions: Decitabine can be used in extramedullary relapse of T-ALL transformed from MDS following allo-PBSCT.

Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies.

Decitabine (5-aza-2'-deoxycytidine) is a hypomethylating agent with a dual mechanism of action: reactivation of silenced genes and differentiation at low doses, and cytotoxicity at high doses. The original studies in the 1980s used decitabine as a classical anticancer drug, at its maximum clinically tolerated dose, 1500 to 2500 mg/m(2) per course. At these doses, decitabine was found to be active in leukemia, but was associated with delayed and prolonged myelosuppression. After a better understanding of epigenetics in cancer and the role of decitabine in epigenetic (hypomethylating) therapy was gained, it was reevaluated at approximately 1/20th of the previous doses (ie, at 'optimal biologic' doses that modulate hypomethylation). In these dose schedules of decitabine (100 to 150 mg/m(2) per course), the drug was found to be active with manageable side effects in patients with myelodysplastic syndromes (MDS) and other myeloid tumors. Optimizing dosing schedules of decitabine to maximize hypomethylation (low dose, high dose intensity, and multiple cycles) have further improved results, suggesting that decitabine is an active therapy that alters the natural course of MDS. Combination therapies that augment the epigenetic effect of decitabine will likely improve responses and extend its use for the treatment of other malignancies.

The role of decitabine in the treatment of myelodysplastic syndromes

Supportive care with red cell and platelet transfusions and use of growth factors has long been the standard of care for patients with myelodysplastic syndromes (MDS) ineligible for stem cell transplantation. Although these measures improve quality of life, their impact on the natural history of the disease is questionable. Recently, three new agents have been approved for the treatment of MDS. These include: 5-azacytidine, lenalidomide and, more recently, 5-aza-2´-deoxycytidine (decitabine). Decitabine is a hypomethylating agent that is incorporated into DNA and forms irreversible covalent adducts with DNA-methyltransferases. At high concentrations, this leads to cell death. At low concentrations, decitabine is considered to exert its anticancer effects by inducing DNA hypomethylation. This results in reactivation of epigenetically repressed genes, such as tumour suppressor genes and, potentially, cell differentiation. In a randomized, Phase III trial of decitabine versus best supportive care in patients with MDS, the overall response rate with decitabine was 17%, including 9% complete remissions. Patients at high risk had a statistically significant prolongation of time to acute myelogenous leukemia transformation or death. This experience has been followed by a study of low-dose decitabine using a five-times daily 1-h infusion schedule, with significant efficacy in patients with MDS observed. Ongoing studies are evaluating the activity and safety of the combination of decitabine with several histone deacetylase inhibitors and other indications. This article summarizes the experience in with decitabine in MDS.

DNA methylation in haematological malignancies: the role of decitabine

Normal cell development and function is dependent upon controlled gene expression. DNA methylation is an epigenetic modification that can play an important role in the control of gene expression. DNA methylation at cytosine residues in gene promoter CpG sequences is known to inhibit gene transcription. Inappropriate inhibition of the transcription of tumour suppressor genes, genes that inhibit angiogenesis and metastasis and genes involved in DNA repair by uncontrolled methylation, can lead to unregulated growth and proliferation of a cell and carcinogenesis. Promoter hypermethylation affecting the p16 gene, resulting in gene silencing, has been shown to occur in many human solid tumours and a ‘hypermethylation profile’ in some leukaemias has been defined. The molecular mechanisms by which aberrant DNA methylation takes place during carcinogenesis are still not clear. However, the large number of target genes (involved in tumorigenesis) that are silenced by aberrant methylation suggests that inhibition of this process may have potential as cancer therapy. Decitabine (NSC-127716, Dacogen™; SuperGen) is a potent and specific hypomethylating agent and an inhibitor of the DNA methyltransferase activity that mediates DNA methylation. Decitabine has been shown to have a broad range of antineoplastic activity in preclinical studies . This agent has exhibited significant activity in the treatment of patients with myelodysplastic syndrome, chronic myeloid leukaemia and acute myeloid leukaemia, although clinical Phase I and II studies with solid tumours have not been very promising. Phase II and III studies are currently ongoing to evaluate decitabine, both alone and in combination, in various stages of these haematological malignancies.

DNA methylation in haematological malignancies: the role of decitabine

DNA methylation in haematological malignancies: the role of decitabine