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Construction and Immunogenicity Testing of Whole Recombinant Yeast-Based T-Cell Vaccines.

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 &gt;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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Arrive: A retrospective registry of Indian patients with venous thromboembolism.

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 &gt;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.

Cell-free Hepatitis B Virus Capsid Assembly Dependent on Core Protein C-Terminal Domain and Regulated by Phosphorylation.

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.

Nonselective inhibition of the epigenetic transcriptional regulator BET induces marked lymphoid and hematopoietic toxicity in mice.

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.

A PHASE I DOSE ESCALATION STUDY EVALUATING THE SAFETY TOLERABILITY AND PHARMACOKINETICS OF CUDC-427, A POTENT, ORAL, MONOVALENT IAP ANTAGONIST, IN PATIENTS WITH REFRACTORY SOLID TUMORS.

To determine the dose-limiting toxicities, adverse events (AE), pharmacokinetics, and preliminary evidence of antitumor activity of CUDC-427 (formerly GDC-0917), a selective antagonist of inhibitor of apoptosis (IAP) proteins.
Patients with advanced solid malignancies were treated with escalating doses of CUDC-427 orally on a daily14-days on/7 days-off schedule in 21-day cycles using a modified continuous reassessment method design. Blood samples were assayed to determine the pharmacokinetic properties, pharmacodynamic alterations of cellular IAP levels in peripheral blood mononuclear cells (PBMCs), and monocyte chemoattractant protein-1 (MCP-1) levels.
Forty-two patients received 119 cycles of CUDC-427. Overall, the most common treatment-related toxicities were fatigue, nausea, vomiting, and rash. One DLT (Grade 3 fatigue) occurred in a patient at 450 mg dose level during cycle 1; and five patients experienced AEs related to CUDC-427 that led to discontinuation and included Grade 3 pruritis, and fatigue, and Grade 2 drug hypersensitivity, pneumonitis, rash, and QT prolongation. The maximum planned dose of 600 mg po daily × 2 weeks was reached, which allometrically scaled to exceed the IC90 in preclinical xenograft studies. Significant decreases in cIAP-1 levels in PBMCs were observed in all patients 6 hours after initial dosing. Responses included durable complete responses (CR) in one patient with ovarian cancer and one patient with MALT lymphoma.
CUDC-427 can be administered safely at doses up to 600 mg daily for 14 days every 3 weeks. The absence of severe toxicities, inhibition of cIAP-1 in PBMC, and antitumor activity warrant further studies.
Copyright ©2016, American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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Author: [email protected]

Construction and Immunogenicity Testing of Whole Recombinant Yeast-Based T-Cell Vaccines.

Arrive: A retrospective registry of Indian patients with venous thromboembolism.

Cell-free Hepatitis B Virus Capsid Assembly Dependent on Core Protein C-Terminal Domain and Regulated by Phosphorylation.

Nonselective inhibition of the epigenetic transcriptional regulator BET induces marked lymphoid and hematopoietic toxicity in mice.

A PHASE I DOSE ESCALATION STUDY EVALUATING THE SAFETY TOLERABILITY AND PHARMACOKINETICS OF CUDC-427, A POTENT, ORAL, MONOVALENT IAP ANTAGONIST, IN PATIENTS WITH REFRACTORY SOLID TUMORS.