Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial.

Activating BRAF(V600E) (Val600Glu) mutations are found in about 1-2% of lung adenocarcinomas, which might provide an opportunity for targeted treatment in these patients. Dabrafenib is an oral selective inhibitor of BRAF kinase. We did a trial to assess the clinical activity of dabrafenib in patients with advanced non-small-cell lung cancer (NSCLC) positive for the BRAF(V600E) mutation.
In this phase 2, multicentre, non-randomised, open-label study, we enrolled previously treated and untreated patients with stage IV metastatic BRAF(V600E)-positive NSCLC. Patients received oral dabrafenib 150 mg twice daily. The primary endpoint was investigator-assessed overall response, which was assessed in patients who had received at least one dose of dabrafenib; safety was also assessed in this population. The study is ongoing but not enrolling patients in this cohort. This trial is registered with ClinicalTrials.gov, number NCT01336634.
Between Aug 3, 2011, and Feb 25, 2014, 84 patients were enrolled, six of whom had not previously received systemic treatment for NSCLC. 26 of the 78 previously treated patients achieved an investigator-assessed overall response (33% [95% CI 23-45]). Four of the six previously untreated patients had an objective response. One patient died from an intracranial haemorrhage that was judged by the investigator to be due to the study drug. Serious adverse events were reported in 35 (42%) of 84 patients. The most frequent grade 3 or worse adverse events were cutaneous squamous-cell carcinoma in ten (12%), asthenia in four (5%), and basal-cell carcinoma in four (5%).
Dabrafenib showed clinical activity in BRAF(V600E)-positive NSCLC. Our findings suggest that dabrafenib could represent a treatment option for a population of patients with limited therapeutic options.
GlaxoSmithKline.
Copyright © 2016 Elsevier Ltd. All rights reserved.

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Gene therapy as a potential tool for treating neuroblastoma-a focused review.

Neuroblastoma, a solid tumor caused by rapid division of undifferentiated neuroblasts, is the most common childhood malignancy affecting children aged <5 years. Several approaches and strategies developed and tested to cure neuroblastoma have met with limited success due to different reasons. Many oncogenes are deregulated during the onset and development of neuroblastoma and thus offer an opportunity to circumvent this disease if the expression of these genes is restored to normalcy. Gene therapy is a powerful tool with the potential to inhibit the deleterious effects of oncogenes by inserting corrected/normal genes into the genome. Both viral and non-viral vector-based gene therapies have been developed and adopted to deliver the target genes into neuroblastoma cells. These attempts have given hope to bringing in a new regime of treatment against neuroblastoma. A few gene-therapy-based treatment strategies have been tested in limited clinical trials yielding some positive results. This mini review is an attempt to provide an overview of the available options of gene therapy to treat neuroblastoma.Cancer Gene Therapy advance online publication, 15 April 2016; doi:10.1038/cgt.2016.16.

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Rational Design, Synthesis, and Biological Evaluation of 7-Azaindole Derivatives as Potent Focused Multi-Targeted Kinase Inhibitors.

Efforts were made to improve a series of potent dual ABL/SRC inhibitors based on a 7-azaindole core with the aim of developing compounds that demonstrate a wider activity on selected oncogenic kinases. Multi-targeted kinase inhibitors (MTKIs) were then derived, focusing on kinases involved in both angiogenesis and tumorigenesis processes. Antiproliferative activity studies using different cellular models led to the discovery of a lead candidate (6z) that combined both antiangiogenic and antitumoral effects. The activity of 6z was assessed against a panel of kinases and cell lines including solid cancers and leukemia cell models to explore its potential therapeutic applications. With its potency and selectivity for oncogenic kinases, 6z was revealed to be a focused MTKI that should have a bright future in fighting a wide range of cancers.

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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.

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Kite Pharma Announces Key Presentations on KTE-C19 and Engineered Cell Therapy Pipeline Programs at the Annual Meeting of the American Association for Cancer Research (AACR)

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