One of the challenges for targeting B-Raf(V600E) with small molecule inhibitors had been achieving adequate selectivity over the wild-type protein B-Raf(WT), as inhibition of the latter has been associated with hyperplasia in normal tissues. Recent studies suggest that B-Raf inhibitors inducing the ‘DFG-in/αC-helix-out’ conformation (Type IIB) likely will exhibit improved selectivity for B-Raf(V600E). To explore this hypothesis, we transformed Type IIA inhibitor (1) into a series of Type IIB inhibitors (sulfonamides and sulfamides 4-6) and examined the SAR. Three selectivity indices were introduced to facilitate the analyses: the B-Raf(V600E)/B-Raf(WT) biochemical ((b)S), cellular ((c)S) selectivity, and the phospho-ERK activation ((p)A). Our data indicates that α-branched sulfonamides and sulfamides show higher selectivities than the linear derivatives. We rationalized this finding based on analysis of structural information from the literature and provided evidence for a monomeric B-Raf-inhibitor complex previously hypothesized to be responsible for the desired B-Raf(V600E) selectivity.
Copyright © 2016 Elsevier Ltd. All rights reserved.

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On April 18, 2016 Advaxis, Inc. (NASDAQ:ADXS), a clinical-stage biotechnology company developing cancer immunotherapies, reported immunological and pathologic data from the Company’s ongoing Phase 2 study of its lead immunotherapy candidate, axalimogene filolisbac (AXAL), in patients with late-stage HPV-associated oropharyngeal cancer (HPVOPC) (Press release, Advaxis, APR 18, 2016, View Source [SID:1234510966]). This phase 2 "window of opportunity" trial was designed to evaluate the effect of AXAL on anti-tumor immunity in the tumor immune microenvironment (TME) of patients with HPVOPC by conducting an analyses and comparison of the TME between pre-treatment tumor biopsy and post-treatment resected tumor tissue, as well as pre and post AXAL treatment blood samples.

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The data were selected for "Late Breaking Abstract" status and will be presented in the poster session of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting on April 18, 2016 from 8:00 AM to 12:00 PM CT in Hall H of the New Orleans Memorial Convention Center in New Orleans, Louisiana. The poster (abstract LB-095) titled "HPV E7 antigen-expressing Listeria-based immunotherapy (AXAL) prior to robotic surgery for HPV-positive oropharyngeal cancer enhances HPV-specific T cell immunity" will be available at www.advaxis.com on Monday, April 18 at 9:00 AM ET.

The Phase 2 study, led by Andrew G. Sikora, M.D., Associate Professor of Otolaryngology and Co-Director of the Head and Neck Cancer Program in the NCI Comprehensive-Designated Dan L. Duncan Cancer Center at Baylor College of Medicine, supported by key investigators Brett Miles, M.D. and Marshall Posner, M.D. at the Icahn School of Medicine at Mount Sinai, and presented at AACR (Free AACR Whitepaper) by Rosemarie Krupar, M.D. from Baylor College of Medicine, evaluates the immunogenicity and differential mechanism of AXAL as preoperative treatment prior to robot-assisted surgery in patients with HPVOPC.

The trial has enrolled eight AXAL-treated patients and six no-treatment observational patients to date, with stage II-IV HPVOPC. The trial uniquely leveraged a 5-6 week "window of opportunity" between diagnosis and TORS (trans-oral robotic surgery) with curative intent, to administer two doses of AXAL treatment at 1x109CFU 2 weeks apart. This unique clinical setting or "window of opportunity", makes it possible to analyze and compare changes to the TME after the compressed regimen of AXAL treatment as well as pre and post treatment blood samples. In this limited timeframe, patients received two doses of AXAL separated by only two weeks, followed by TOR surgery 1-2 weeks after the second dose.

The data presented showed that HPV E7- and/or E6-specific T cell responses increased in the peripheral blood in five of the study patients. Increased infiltration of both CD4+ and CD8+ T cells were observed in the TME of four patients, with a reduction of FOXP3+ regulatory T cells within the tumors of 3/6 patients. Increased T cell responses to HPV E6 supports enhanced immune activity against additional tumor targets. Changes to the TME included cytotoxic T cell infiltration into the post-resection tumor, increased immune activation, a reduction of regulatory T cells, infiltration of cytotoxic T cells, and increased expression of inflammatory activation markers. In addition, fluctuations of circulating serum cytokine (IL-15, IL-9, TNfa, IL-2 and MIP-1b) levels were observed potentially suggesting consumption by activated T cells and migration of T cells to the TME.

"While our data is preliminary, in several patients we saw increased T cell response, evidence of epitope spreading, and signs of increased immune activation consistent with expansion and infiltration of activated T cells into the tumor. We also saw trends towards a reduction in immuno-suppressive Tregs. Importantly, in several patients when compared to pre-treatment tumor tissue, post-treatment tissue analysis showed conversion of the TME into a site of active inflammation characterized by infiltration of activated T cells, and increased expression of activation markers including PD-1, PD-L1," said Andrew Sikora, M.D., Ph.D., Associate Professor of Otolaryngology at the Baylor College of Medicine. "The fact that we are seeing these trends at this preliminary point in the study is very encouraging, and suggests that AXAL has the potential to generate beneficial immunologic responses in patients with HPV+ head and neck cancer."

"The biggest challenge for an effective cancer immunotherapy is to overcome the mechanisms tumors use to protect themselves from immunological attack and destruction. Researchers refer to this as ‘immunosuppression in the tumor microenvironment (or TME).’ It has been demonstrated and published in peer review journals that Advaxis’ Lm Technology enables cytotoxic T cells to infiltrate into the TME. The late breaking AXAL data shows – for the first time in a human clinical trial – the potential of the Lm Technology platform to elicit a targeted anti-cancer immune response with clear infiltration into the TME by cytotoxic T cells," said Daniel J. O’Connor, President and Chief Executive Officer of Advaxis.

"This is the first human clinical data that replicates the multiple beneficial immunologic and tumor microenvironment-modifying aspects of treatment with Advaxis’ immunotherapies that have been consistently demonstrated in several research models. It’s impressive that these changes occurred so consistently despite being obliged to use a shortened treatment schedule without the usual follow-up period to fit within the ‘window.’ Immunotherapies are generally understood to work better over time, and we would expect these early beneficial effects to deepen and contribute to tumor-controlling immunity over time," said Robert Petit, Chief Scientific Officer and EVP of Advaxis. "These data points are the first clear demonstration of the reduction of Tregs in human tumors associated with Advaxis’ immunotherapy. Inhibition of Tregs has been clearly associated with the Advaxis tLLO fusion peptide in many publications. Immune activation through TLRs and PAMPS, including STING and the subsequent infiltration of tumor fighting T cells into the TME along and simultaneous reduction in tumor protection by Tregs, are the cornerstones of successful immunotherapies. Every Advaxis immunotherapy product candidate, including AXAL, has these elements built into it."

The study received a three-year $1.1 million grant from the U.S. Food and Drug Administration’s Office of Orphan Products Development, which funds research for the development of products for rare diseases.

For additional information, Advaxis will host a Research Reception at AACR (Free AACR Whitepaper) at 6:30 PM CT on April 18, 2016 at the Sheraton New Orleans Hotel in New Orleans, Louisiana.

About Axalimogene Filolisbac

Axalimogene filolisbac (AXAL) is Advaxis’ lead Lm Technology immunotherapy candidate for the treatment of HPV-associated cancers and is in clinical trials for three potential indications: invasive cervical cancer, head and neck cancer, and anal cancer. In a completed randomized Phase 2 study in recurrent/refractory cervical cancer, axalimogene filolisbac showed apparent prolonged survival, objective tumor responses, and a manageable safety profile alone or in combination with chemotherapy, supporting further development of the company’s Lm Technology. Axalimogene filolisbac has Orphan Drug Designation in the U.S. for the treatment of anal cancer.

On April 18, 2016 bluebird bio, Inc. (Nasdaq: BLUE), a clinical-stage company committed to developing potentially transformative gene therapies for severe genetic and rare diseases and T cell-based immunotherapies for cancer, reported that data from clinical, preclinical, and research and manufacturing programs will be highlighted in ten presentations at the American Society of Gene & Cell Therapy (ASGCT) (Free ASGCT Whitepaper) 19th Annual Meeting, taking place May 4-7, 2016 in Washington, D.C (Press release, bluebird bio, APR 18, 2016, View Source;p=RssLanding&cat=news&id=2158031 [SID:1234510988]).

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Two oral presentations given by bluebird’s academic collaborators will highlight previously presented data from bluebird bio’s ongoing gene therapy clinical trials. David Williams, M.D., chief of hematology/oncology at Boston Children’s Hospital will present interim data from the Starbeam Study of Lenti-D in cerebral adrenoleukodystrophy, and Marina Cavazzana, M.D., Ph.D., of Hospital Necker, University Paris Descartes, will present interim data from the HGB-205 study of LentiGlobin in severe sickle cell disease and transfusion-dependent β-thalassemia.

Eight additional presentations will be featured at the meeting, highlighting progress across the company’s preclinical, research and process development activities.

"As bluebird continues to build a differentiated T cell oncology franchise, we are excited to present three oncology abstracts that highlight our work on the next generation of technology for T cell-based immunotherapy – including methods of generating T cells with sustained anti-tumor activity, small-molecule regulated chimeric antigen receptors (CARs) and genome editing to generate improved CAR T cells," said Philip Gregory, D.Phil., chief scientific officer, bluebird bio. "From our hematopoietic stem cell programs, we will also share updates in five presentations covering improvements in scalable manufacturing, transduction efficiency and assay development – critical areas for making gene therapy available to more patients."

The abstracts are now available online on the ASGCT (Free ASGCT Whitepaper) Annual Meeting website.

Details of bluebird bio’s oral presentations are as follows:

Title: A Phase 2/3 Study of the Efficacy and Safety of Ex Vivo Gene Therapy With Lenti-D Lentiviral Vector for the Treatment of Cerebral Adrenoleukodystrophy
Abstract Number: 250
Session: Clinical Trials Spotlight Symposium
Date: Thursday, May 5, 2016
Time: 9:00 – 9:20 a.m.
Location: Thurgood Marshall North/East
Note: Data previously presented at the 2016 American Academy of Neurology Annual Meeting

Title: Small Molecule-regulated Antigen Recognition System for Inducible T Cell Targeting of Cancer Cells
Abstract Number: 277
Session: Cancer-Immunotherapy, Cancer Vaccines I
Date: Thursday, May 5, 2016
Time: 5:15 – 5:30 p.m.
Location: Washington 4

Title: Clinical Outcomes of Gene Therapy with BB305 Lentiviral Vector for Sickle Cell Disease and β-Thalassemia
Abstract Number: 279
Session: Hematologic & Immunologic Diseases I
Date: Thursday, May 5, 2016
Time: 4:00 – 4:15 p.m.
Location: Washington 5-6
Note: Data previously presented at the 2015 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting

Title: Towards the Clinical Application of BCMA CAR T cells: The Importance of Reduced Tonic Signaling and Methods to Enhance Memory T Cells
Abstract Number: 747
Session: Cancer-Immunotherapy, Cancer Vaccines III
Date: Saturday, May 7, 2016
Time: 10:45 – 11:00 a.m.
Location: Thurgood Marshall North

Details of bluebird bio’s poster presentations are as follows:

Title: PGE2 Increases Lentiviral Vector Transduction Efficiency of Human HSC
Abstract Number: 229
Session: Hematologic & Immunologic Diseases I
Date: Wednesday, May 4, 2016
Time: 5:30 p.m. – 7:30 p.m.
Location: Exhibit Hall C & B South

Title: Staurosporine Increases Lentiviral Transduction of Human CD34+ Cells
Abstract Number: 221
Session: Hematologic & Immunologic Diseases I
Date: Wednesday, May 4, 2016
Time: 5:30 p.m. – 7:30 p.m.
Location: Exhibit Hall C & B South

Title: Qualification of a p24 ELISA Assay for Quantitation of Total Lentiviral Vector Concentration
Abstract Number: 473
Session: Pharmacology/Toxicology Studies or Assay Development
Date: Thursday, May 5, 2016
Time: 6:00 p.m. – 8:00 p.m.
Location: Exhibit Hall C & B South

Title: Efficient Generation of CART Cells by Homology Directed Transgene Integration into the TCR-Alpha Locus
Abstract Number: 323
Session: Targeted Genome Editing II
Date: Thursday, May 5, 2016
Time: 6:00 p.m. – 8:00 p.m.
Location: Exhibit Hall C & B South

Title: Development of a Stable Producer Cell Line for Scalable Lentiviral Vector Production for Gene Therapy of Hemoglobinopathies
Abstract Number: 458
Session: Vector and Cell Engineering/Manufacturing I
Date: Thursday, May 5, 2016
Time: 6:00 p.m. – 8:00 p.m.
Location: Exhibit Hall C & B South

Title: Characterization of Nanoparticles in Lentiviral Vector Preparations
Abstract Number: 709
Session: Vector and Cell Engineering/Manufacturing II
Date: Friday, May 6, 2016
Time: 6:00 p.m. – 8:00 p.m.
Location: Exhibit Hall C & B South

On April 18, 2016 AstraZeneca reported new data from multiple molecules in its industry-leading DNA Damage Response (DDR) pipeline at the 2016 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, LA (Press release, AstraZeneca, APR 18, 2016, View Source [SID:1234511011]). These agents use a variety of different pathways to disrupt tumour cells’ natural ability to repair themselves as they replicate, eventually causing the tumour cells to die.7,8 Illustrating the unique breadth of AstraZeneca’s approaches to DDR, presentations at AACR (Free AACR Whitepaper) featured molecules that disrupt multiple tumour cell repair processes, including single-strand break repair, double-strand break repair, and cell cycle regulation.1-6

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Susan Galbraith, Head of AstraZeneca’s Oncology Innovative Medicines Unit said, "Taken together with the positive Phase II results of olaparib in patients with metastatic, castration-resistant prostate cancer published early this year,9 we are encouraged by the potential of PARP inhibition in multiple tumour types beyond ovarian cancer. The breadth of our pipeline showcases DDR monotherapies and combinations that could attack cancer in a multitude of novel ways – our first priority, as demonstrated here at AACR (Free AACR Whitepaper), is to follow the science to identify and quickly advance those molecules that have the potential to address the greatest unmet medical needs."

PARP Inhibition and Lynparza (olaparib): Beyond Ovarian Cancer

The PARP inhibitor olaparib is the cornerstone of AstraZeneca’s pipeline of personalised treatments targeting DDR mechanisms in cancer cells. Olaparib was combined with the investigational AKT inhibitor AZD5363 in a new Phase I trial of germline (g) BRCA and non-BRCA mutant (m) advanced cancer patients with ovarian, breast, prostate and bile duct cancers.1 Results showed that the olaparib-AZD5363 combination was well-tolerated with multiple responses, including 10 RECIST complete or partial responses (out of 37 evaluable patients) in both gBRCA and non-BRCAm tumours, as well as prior PARP inhibitor-treated cancers.1

Olaparib disrupts the repair of single-strand DNA breaks, a mode of action that has potential to work in a range of tumour types beyond ovarian cancer.10 AstraZeneca is researching how several different compounds can be combined with DDR molecules to provide a dual threat to tumour cells. For example, treatments such as AZD5363 that selectively inhibit the PI3K / AKT signalling pathway may complement olaparib’s interference with tumour DNA repair.1

Additional Mechanisms of DDR: Cell Cycle Disruption & Double-Strand Break Repair

AstraZeneca presented data on a variety of investigational compounds acting on different aspects of the DDR pathway, both in monotherapy and in combination. Most significant were early results from a Phase Ib open-label study of AZD1775, a novel small molecule designed to inhibit the Wee1 kinase.2 Wee1 is a protein kinase that helps regulate the cell cycle.5 In many tumours, Wee1 overexpression stops the cell cycle after DNA damage occurs, allowing tumour cells time to repair any damage.5,11 By inhibiting Wee1, the cell cycle continues despite damage, which can lead to tumour cell death.5 Assessing the safety, tolerability, pharmacokinetics and anti-tumour activity of AZD1775, the Phase Ib safety run-in included patients with small-cell lung, non-small cell lung, head and neck, ovarian, breast, pancreas and unknown primary tumours.2 Early results demonstrated a partial or stable response in a third of patients (4/12), and AstraZeneca has initiated expansion cohorts in ovarian, breast and small-cell lung cancer.2 Other studies currently recruiting include a Phase I multi-centre, dose escalation study of AZD1775 combined with olaparib in refractory solid tumours.12

Several other new molecules in the clinical pipeline are entering Phase I development, including the first-in-class Ataxia telangiectasia mutated (ATM) kinase inhibitor AZD0156.3 Pre-clinical in vivo activity of AZD0156 presented at AACR (Free AACR Whitepaper) demonstrated that inhibition of ATM during the DNA damage response enhanced the efficacy of a range of DNA-damaging agents, including olaparib, and support its further study in the clinical setting.3 AstraZeneca is now recruiting for a Phase I trial of AZD0156 as monotherapy or in combination with olaparib in patients with advanced solid tumours.13

Other ongoing DDR-focused studies include additional Phase I trials of the Aurora B kinase inhibitor AZD281114 and ATR inhibitor AZD6738 in solid tumours.15

In this analysis, we compared costs and explored the cost-effectiveness of subsequent-line treatment with cetuximab or panitumumab in patients with wild-type KRAS (exon 2) metastatic colorectal cancer (mCRC) after previous chemotherapy treatment failure. Data were used from ASPECCT (A Study of Panitumumab Efficacy and Safety Compared to Cetuximab in Patients With KRAS Wild-Type Metastatic Colorectal Cancer), a Phase III, head-to-head randomized noninferiority study comparing the efficacy and safety of panitumumab and cetuximab in this population.
A decision-analytic model was developed to perform a cost-minimization analysis and a semi-Markov model was created to evaluate the cost-effectiveness of panitumumab monotherapy versus cetuximab monotherapy in chemotherapy-resistant wild-type KRAS (exon 2) mCRC. The cost-minimization model assumed equivalent efficacy (progression-free survival) based on data from ASPECCT. The cost-effectiveness analysis was conducted with the full information (uncertainty) from ASPECCT. Both analyses were conducted from a US third-party payer perspective and calculated average anti-epidermal growth factor receptor doses from ASPECCT. Costs associated with drug acquisition, treatment administration (every 2 weeks for panitumumab, weekly for cetuximab), and incidence of infusion reactions were estimated in both models. The cost-effectiveness model also included physician visits, disease progression monitoring, best supportive care, and end-of-life costs and utility weights estimated from EuroQol 5-Dimension questionnaire responses from ASPECCT.
The cost-minimization model results demonstrated lower projected costs for patients who received panitumumab versus cetuximab, with a projected cost savings of $9468 (16.5%) per panitumumab-treated patient. In the cost-effectiveness model, the incremental cost per quality-adjusted life-year gained revealed panitumumab to be less costly, with marginally better outcomes than cetuximab.
These economic analyses comparing panitumumab and cetuximab in chemorefractory wild-type KRAS (exon 2) mCRC suggest benefits in favor of panitumumab. ClinicalTrials.gov identifier: NCT01001377.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

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