Bromo and extra terminal (BET) proteins (BRD2, BRD3, BRD4 and BRDT) are epigenetic transcriptional regulators required for efficient expression of growth promoting, cell cycle progression and antiapoptotic genes. Through their bromodomain, these proteins bind to acetylated lysine residues of histones and are recruited to transcriptionally active chromatin. Inhibition of the BET-histone interaction provides a tractable therapeutic strategy to treat diseases that may have epigenetic dysregulation. JQ1 is a small molecule that blocks BET interaction with histones. It has been shown to decrease proliferation of patient-derived multiple myeloma in vitro and to decrease tumor burden in vivo in xenograft mouse models. While targeting BET appears to be a viable and efficacious approach, the nonclinical safety profile of BET inhibition remains to be well-defined. We report that mice dosed with JQ1 at efficacious exposures demonstrate dose-dependent decreases in their lymphoid and immune cell compartments. At higher doses, JQ1 was not tolerated and due to induction of significant body weight loss led to early euthanasia. Flow cytometry analysis of lymphoid tissues showed a decrease in both B- and T-lymphocytes with a concomitant decrease in peripheral white blood cells that was confirmed by hematology. Further investigation with the inactive enantiomer of JQ1 showed that these in vivo effects were on-target mediated and not elicited through secondary pharmacology due to chemical structure.
Copyright © 2016 Elsevier Inc. All rights reserved.

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Multiple subunits of the hepatitis B virus (HBV) core protein (HBc) assemble into an icosahedral capsid that packages the viral pregenomic RNA (pgRNA). The N-terminal domain (NTD) of HBc is sufficient for capsid assembly, in the absence of pgRNA or any other viral or host factors, under conditions of high HBc and/or salt concentrations. The C-terminal domain (CTD) is deemed dispensable for capsid assembly although it is essential for pgRNA packaging. We report here that HBc expressed in a mammalian cell lysate, the rabbit reticulocyte lysate (RRL), was able to assemble into capsids when HBc concentrations (in low nM) mimicked those achieved under conditions of viral replication in vivo and were far below those used previously for capsid assembly in vitro. Furthermore, at physiologically low HBc concentrations in RRL, NTD was insufficient for capsid assembly and CTD was also required. CTD likely facilitated assembly under these conditions via RNA binding and protein-protein interactions. Moreover, CTD underwent phosphorylation and dephosphorylation events in RRL as in vivo, which regulated capsid assembly. Importantly, NTD alone also failed to accumulate in mammalian cells, likely resulting from its failure to assemble efficiently. Co-expression of the full-length HBc rescued NTD assembly in RRL as well as NTD expression and assembly in mammalian cells, resulting in the formation of mosaic capsids containing both full-length HBc and NTD. These results have important implications for HBV assembly during replication and provide a facile cell-free system to study capsid assembly under physiologically relevant conditions including its modulation by host factors.
Hepatitis B virus (HBV) is an important global human pathogen and the main cause of liver cancer worldwide. An essential component of HBV is the spherical capsid composed of multiple copies of a single protein, the core protein (HBc). We have developed a mammalian cell-free system in which HBc is expressed at physiological (low) concentrations and assemble into capsids under near physiological conditions. In this cell-free system, as in mammalian cells, capsid assembly depends on the C-terminal domains (CTD) of HBc, in contrast to other assembly systems in which HBc assembles into capsids independent of CTD under non-physiological protein and salt concentrations. Furthermore, the phosphorylation state of CTD regulates capsid assembly and RNA encapsidation, in the cell-free system as in mammalian cells. This system will facilitate detailed studies on capsid assembly and RNA encapsidation under physiological conditions and identification of antiviral agents that target HBc.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.

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On April 15, 2016 Kite Pharma, Inc., (Nasdaq:KITE) ("Kite") a clinical-stage biopharmaceutical company focused on developing engineered autologous T cell therapy (eACT) products for the treatment of cancer, reported the schedule of presentations and addresses related to its engineered cell therapy programs at the upcoming AACR (Free AACR Whitepaper) Annual Meeting in New Orleans, Louisiana (Press release, Kite Pharma, APR 15, 2016, View Source [SID:1234510955]). Topics will include KTE-C19, Kite’s lead chimeric antigen receptor (CAR) product candidate, as well as engineered T cell receptor (TCR) product candidates targeting solid tumors that express the MAGE-A3 and KRAS cancer proteins. KTE-C19 is currently being studied in four pivotal clinical trials. Clinical study of the MAGE-A3 TCR and pre-clinical study of KRAS TCRs are being advanced as part of a Cooperative Research and Development Agreement (CRADA) between Kite and the National Cancer Institute.

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Oral Presentations

Updated Phase 1 Results from ZUMA-1: A Phase 1-2 Multi-Center Study Evaluating the Safety and Efficacy of KTE-C19 (Anti-CD19 CAR T Cells) in Subjects with Refractory Aggressive Non-Hodgkin Lymphoma (NHL)
Date: April 19, 2016, 4:00 – 4:15PM Central Time
Session: Early Clinical Trials Evaluating Cell-based, Checkpoint Inhibitors, and Novel Immunotherapeutics
Abstract Number: CT135
Location: Room 343, Morial Convention Center
Presenter: Armin Ghobadi, M.D., Washington University, St. Louis, MO

A Phase 1 Study of an HLA-DPB1*0401-restricted T Cell Receptor Targeting MAGE-A3 for Patients with Metastatic Cancer
Date: April 17, 2016, 3:15 – 3:35PM Central Time
Session: Immuno-Oncology Clinical Trials I
Abstract Number: CT003
Location: La Nouvelle Orleans Ballroom, Morial Convention Center
Presenter: Yong-Chen W. Lu, Ph.D., Surgery Branch, National Cancer Institute

Session Presentations

Plenary Session: T Cell Recognition of Human Cancer
Date: April 17, 2016, 11:00 – 11:30AM Central Time
Session: PL01 Opening Plenary – Breakthroughs in Cancer Research: Genomics, Epigenetics, and Immunomodulation
Location: Hall F, Morial Convention Center
Speaker: Ton Schumacher, Ph.D., Netherlands Cancer Institute

Targeting Cancers with Engineered T Cells or BiTES: Towards Broader Application
Date: April 18, 2016, 5:00 – 6:30PM Central Time
Session: Forum FO09
Location: La Nouvelle Orleans Ballroom, Morial Convention Center
Invited Speaker: David Chang, M.D., Ph.D., Kite Pharma

Poster Presentations

Manufacturing and Characterization of KTE-C19 in a Multicenter Trial of Subjects with Refractory Aggressive Non-Hodgkin’s Lymphoma (NHL) (ZUMA-1)
Date: April 18, 2016, 1:00 – 5:00PM Central Time
Session: Adoptive Cell Therapy
Abstract Number: 2308
Location: Poster Hall, Section 25, Poster Board 20
Presenter: John M. Rossi, Kite Pharma

Comparative Evaluation of Peripheral Blood T Cells and Resultant Engineered Anti-CD19 CAR T Cell Products from Relapsed/Refractory Non-Hodgkin’s Lymphoma (NHL) Patients
Date: April 18, 2016, 1:00 – 5:00PM Central Time
Session: Adoptive Cell Therapy
Abstract Number: 2305
Location: Poster Hall, Section 25, Poster Board 17
Presenter: Timothy J. Langer, Kite Pharma

Identification of T-cell Receptors Targeting KRAS-mutated Human Tumors
Date: April 19, 2016, 8:00AM – 12:00PM Central Time
Session: Late-Breaking Research: Experimental and Molecular Therapeutics 3
Abstract Number: LB-242
Location: Poster Hall, Section 11, Poster Board 22
Presenters: James C. Yang, M.D., National Cancer Institute, National Institutes of Health

There is lack of substantial Indian data on venous thromboembolism (VTE). The aim of this study was to provide real-world information on patient characteristics, management strategies, clinical outcomes, and temporal trends in VTE.
Multicentre retrospective registry involving 549 medical records of patients with confirmed diagnosis of VTE (deep vein thrombosis [DVT] confirmed by Doppler ultrasonography; pulmonary embolism [PE] by computed tomography, pulmonary angiography and/or V/Q scan) from 2006 to 2010 at three Indian tertiary care hospitals.
Acute DVT without PE, acute DVT with PE, and PE alone were reported in 64% (352/549), 23% (124/549), and 13% (73/549) patients, respectively. Mean age was 47 (±16) years, and 70% were males. H/o DVT (34%), surgery including orthopedic surgery (28%), trauma (16%), and immobilization >3 days (14%) were the most common risk factors for VTE. Hypertension (25%), diabetes (19%), and neurological disease (other than stroke) (8%) were the most common co-morbidities. Most (94%) were treated with heparin alone (82%) or fondaparinux (2%) for initial anticoagulation; low molecular weight heparin alone (5%) or warfarin/acenocoumarol (76%) for long-term anticoagulation. Anticoagulant treatment was stopped because of bleeding in 2% (9/515) patients. Mortality was 7% among patients diagnosed with VTE during hospital stay versus 1% in those hospitalized with diagnosed VTE. The annual incidence of DVT (±PE) increased from 2006 to 2010.
Acute DVT alone was responsible for the substantial burden of VTE in Indian patients. Bleeding was not the limiting factor for anticoagulant treatment in most patients.

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GlobeImmune’s Tarmogen() immunotherapy platform utilizes recombinant Saccharomyces cerevisiae yeast as a vaccine vector to deliver heterologous antigens for activation of disease-specific, targeted cellular immunity. The vaccines elicit immune-mediated killing of target cells expressing viral and cancer antigens in vivo via a CD8(+) CTL-mediated mechanism. Tarmogens are not neutralized by host immune responses and can be administered repeatedly to boost antigen-specific immunity. Production of the vaccines yields stable off-the-shelf products that avoid the need for patient-specific manufacturing found with other immunotherapeutic approaches. Tarmogens for the treatment of chronic hepatitis B and C and various cancers were well tolerated and immunogenic in phase 1 and 2 clinical trials encompassing >600 subjects. The platform is being widely utilized in basic vaccine research and the most rapid path to success in these endeavors follows from optimal immunoassay selection and execution. This chapter provides detailed methods for the construction and preclinical immunogenicity testing of yeast-based immunotherapeutic products to support the rapid and efficient use of this versatile technology.

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