ABSTRACT
PURPOSE: The histone deacetylase (HDAC) inhibitor panobinostat potentiates anthracycline and cytarabine cytotoxicity in acute myeloid leukemia (AML) cells. We hypothesized that panobinostat prior to and during induction chemotherapy would be tolerable and augment response in patients showing increased histone acetylation. PATIENTS AND METHODS: Patients received panobinostat 20-60 mg oral daily on days 1, 3, 5, and 8 with daunorubicin 60 mg/m2/day intravenously on days 3 to 5 and cytarabine 100 mg/m2/day intravenously by continuous infusion on days 3 to 9 ("7+3"). Peripheral blood mononuclear cells (PBMCs) were isolated for HDAC expression and histone acetylation changes. RESULTS: Twenty-five patients ages 60-85 years (median age, 69) were treated. Fifteen patients had de novo AML, six AML with myelodysplasia-related changes, two AML with prior myeloproliferative neoplasm, one therapy-related myeloid neoplasm, and one myelodysplastic syndrome with excess blasts-2. No dose-limiting toxicities occurred in dose escalation cohorts. In dose expansion, six patients received panobinostat at 60 mg and nine patients at 50 mg due to recurrent grade 1 bradycardia at the 60-mg dose. The complete response (CR)/incomplete count recovery (Cri) rate was 32%. Median overall survival was 10 months: 23 months with CR/CRi versus 7.8 months without CR/CRi (log-rank P = 0.02). Median relapse-free survival was 8.2 months. Increased histone acetylation 4 and 24 hours after panobinostat was significantly associated with CR/CRi. CONCLUSIONS: Panobinostat with "7+3" for older patients with AML was well tolerated. Panobinostat 50 mg on days 1, 3, 5, and 8 starting 2 days prior to "7+3" is recommended for future studies. Panobinostat-induced increases in histone acetylation in PBMCs predicted CR/CRi.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Acetylation , Age Factors , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Drug Monitoring , Female , Gene Expression , Histone Deacetylase Inhibitors/administration & dosage , Histone Deacetylase Inhibitors/pharmacokinetics , Histones/genetics , Histones/metabolism , Humans , Induction Chemotherapy , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Prognosis , Remission Induction , Treatment OutcomeABSTRACT
Autoimmune diabetes mellitus (DM) results from the destruction of pancreatic islet cells by activated T lymphocytes, which have been primed by activated dendritic cells (DC). Individualized therapy with ex vivo DC manipulation and reinfusion has been proposed as a treatment for DM, but this treatment is limited by cost, and requires specialized facilities. A means of in situ modulation of the DC phenotype in the host would be more accessible. Here we report a novel innate immune modulator, 1Z1, generated by conjugating a TLR7 ligand to six units of polyethylene glycol (PEG), which skews DC phenotype in vivo. 1Z1 was less potent in inducing cytokine production by DC than the parent ligand in vitro and in vivo. In addition, this drug only modestly increased DC surface expression of activation markers such as MHC class II, CD80, and CD86; however, the expression of negative regulatory molecules, such as programmed death ligand 1 (PD-L1), and interleukin-1 receptor-associated kinase M (IRAK-M) were markedly increased. In vivo transfer of 1Z1 treated DC into prediabetic NOD mice delayed pancreatic insulitis. Daily administration of 1Z1 effectively prevented the clinical onset of hyperglycemia and reduced histologic islet inflammation. Daily treatment with 1Z1 increased PD-L1 expression in the CD11c(+) population in peri-pancreatic lymph nodes; however, it did not induce an increase in regulatory T cells. Pharmaceutical modulation of DC maturation and function in situ, thus represents an opportunity to treat autoimmune disease.
Subject(s)
Dendritic Cells/immunology , Dendritic Cells/metabolism , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/metabolism , Immune Tolerance , Toll-Like Receptor 7/metabolism , Adoptive Transfer , Animals , B7-H1 Antigen/genetics , B7-H1 Antigen/metabolism , Cytokines/metabolism , Dendritic Cells/drug effects , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/therapy , Disease Models, Animal , Female , Gene Expression , Immunity, Innate , Immunomodulation , Inflammation Mediators/metabolism , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Ligands , Lymphocyte Activation/immunology , Mice , Mice, Inbred NOD , Mice, Knockout , Phenotype , T-Lymphocyte Subsets/drug effects , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Toll-Like Receptor 7/geneticsABSTRACT
BACKGROUND: The Toll-like receptor 7 (TLR7) activator imiquimod (IMQ) is safe and effective in treating actinic keratosis; however, an intermittent treatment regimen is necessary because of excessive local reactions. OBJECTIVES: To evaluate in vitro potency, pharmacodynamics/pharmacokinetics, toxicity and efficacy in vivo of the newly developed TLR7 ligand-phospholipid conjugate, TMX-202, in a gel formulation. MATERIAL AND METHODS: The effects of TMX-202 were assessed both in vitro on a murine macrophage cell line and in primary bone marrow-derived dendritic cells and in vivo on mice (C57BL/6-wild type, Myd88(-/-) and Tlr7(-/-)). RESULTS: TMX-202 was more potent than IMQ in vitro using murine and human cells. In contrast, in vivo it showed less systemic pro-inflammatory activity and better safety than IMQ. Moreover, the TMX-202 gel formulation exhibited at least comparable efficacy to Aldara in a mouse model for skin proliferative diseases. CONCLUSION: TMX-202 is safe and efficacious without causing excessive adverse effects, suggesting that it may be an alternative to Aldara for the treatment of proliferative skin conditions.
