On April 21, 2016 TapImmune,Inc. (TPIV), a clinical-stage immunology-oncology company specializing in the development of innovative peptide and gene-based immunotherapeutics and vaccines for the treatment of cancer & metastatic disease, reported plans to initiate a Phase 2 trial of its cancer vaccine, TPIV 200, a multi-epitope anti-folate receptor vaccine (FRalfa), in combination with Astra Zeneca (NYSE: AZN) durvalumab (MEDI4736), an anti-PD-L1 antibody, in patients with platinum-resistant ovarian cancer (Press release, TapImmune, APR 21, 2016, View Source [SID:1234512243]). The study will commence in the second quarter of 2016 at Memorial Sloan Kettering Cancer Center in New York and will be led by Jason Konner, M.D. as Principal Investigator.

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The two Companies will share clinical costs, while TapImmune will supply TPIV 200 and MedImmune will supply Durvalumab (MED14736) for the trials. TapImmune recently obtained Orphan Drug Designation for TPIV 200 in ovarian cancer from the U.S. Food and Drug Administration.

This single arm Phase 2 trial will include 40 women with high-grade ovarian, tubal, or primary peritoneal carcinomas, who have progressed within 6 months of their most recent platinum chemotherapy. The primary objective of the study is to determine the effectiveness of the combination by measuring Overall Response Rate [ORR = Complete Response (CR) + Partial Response (PR)] by RECIST and Progression Free Survival (PFS) rate at 6 months. Secondary endpoints will be safety and immune and correlation of FRalfa-specific immune responses with clinical efficacy.

"This collaboration is a significant event for TapImmune," stated Dr. Glynn Wilson, Chairman and CEO of TapImmune. "We are delighted to bring a leading T-cell vaccine platform into this combination study and to work with AstraZeneca/Medimmune and Sloan Kettering in a patient population that is in dire need of an effective treatment."

"This study is part of a larger Phase 2 strategy for TPIV 200 that is designed to greatly increase our understanding of the vaccine while providing clinical evidence of efficacy," Dr. Wilson added.

TPIV 200 is a multi-epitope peptide vaccine that targets Folate Receptor Alpha, which is overexpressed in multiple cancers including over 90% of ovarian cancer cells. In Phase I clinical studies conducted at the Mayo Clinic in patients with breast and ovarian cancer, this vaccine was shown to be safe and well tolerated and to give robust cellular immune responses in 20 out of 21 evaluable patients.

About Durvalumab (MEDI4736)

Durvalumab is an investigational human monoclonal antibody directed against PD-L1 developed at MedImmune LLC. Signals from PD-L1 help tumors avoid detection by the immune system. Durvalumab blocks these signals, countering the tumor’s immune-evading tactics. Durvalumab is being developed, alongside other immunotherapies, to empower the patient’s immune system and attack the cancer. Durvalumab is being investigated in an extensive clinical trial program, as monotherapy or in combination with tremelimumab, in NSCLC, head and neck, gastric, pancreatic, bladder and blood cancers.

Small cell lung cancer (SCLC) is an aggressive disease with poor survival. A few sequencing studies performed on limited number of samples have revealed potential disease-driving genes in SCLC, however, much still remains unknown, particularly in the Asian patient population. Here we conducted whole exome sequencing (WES) and transcriptomic sequencing of primary tumors from 99 Chinese SCLC patients. Dysregulation of tumor suppressor genes TP53 and RB1 was observed in 82% and 62% of SCLC patients, respectively, and more than half of the SCLC patients (62%) harbored TP53 and RB1 mutation and/or copy number loss. Additionally, Serine/Arginine Splicing Factor 1 (SRSF1) DNA copy number gain and mRNA over-expression was strongly associated with poor survival using both discovery and validation patient cohorts. Functional studies in vitro and in vivo demonstrate that SRSF1 is important for tumorigenicity of SCLC and may play a key role in DNA repair and chemo-sensitivity. These results strongly support SRSF1 as a prognostic biomarker in SCLC and provide a rationale for personalized therapy in SCLC.

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Multi-modality imaging methods are of great importance in oncologic studies for acquiring complementary information, enhancing the efficacy in tumor detection and characterization. We hereby demonstrate a hybrid non-invasive in vivo imaging approach of utilizing magnetic resonance imaging (MRI) and Multispectral Optoacoustic Tomography (MSOT) for molecular imaging of glucose uptake in an orthotopic glioblastoma in mouse. The molecular and functional information from MSOT can be overlaid on MRI anatomy via image coregistration to provide insights into probe uptake in the brain, which is verified by ex vivo fluorescence imaging and histological validation. In vivo MSOT and MRI imaging of an orthotopic glioma mouse model injected with IRDye800-2DG. Image coregistration between MSOT and MRI enables multifaceted (anatomical, functional, molecular) information from MSOT to be overlaid on MRI anatomy images to derive tumor physiological parameters such as perfusion, haemoglobin and oxygenation.
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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On April 20, 2016 – OncoMed Pharmaceuticals Inc. (NASDAQ:OMED), presented new biomarker research associated with its clinical programs for anti-RSPO3 (OMP-131R10) and vantictumab (anti-FZD7, OMP-18R5), as well as new preclinical mechanism-of-action data for demcizumab (anti-DLL4, OMP-18M21), at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Meeting (Press release, OncoMed, APR 20, 2016, View Source [SID:1234511148]). All three presentations support ongoing clinical trials: anti-RSPO3 in a Phase1a/b trial in advanced solid tumor and colorectal cancer; vantictumab in a Phase 1b trial in pancreatic cancer; and demcizumab in a Phase 2 randomized study in first-line non-small cell lung cancer (NSCLC).

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Based on preclinical work in patient-derived xenograft models that demonstrated a correlation between RSPO3 gene expression and anti-RSPO3 antibody efficacy, researchers at OncoMed set out to develop predictive biomarker assays. A CLIA-validated RSPO3 assay and a gene fusion detection workflow have both been developed and are now being deployed in OncoMed’s Phase 1a/1b dose escalation study of anti-RSPO3 in advanced solid tumors and in combination with FOLFIRI in metastatic colorectal cancer. Data detailing the validation of the predictive biomarker tests were presented in Abstract 404: "Development of a RSPO3 CLIA-validated assay as a predictive biomarker for response to anti-RSPO3 antibody treatment in patients with solid tumors".

Abstract 3129: "Predictive biomarker identification for response to vantictumab (OMP-18R5; anti-Frizzled) using primary patient-derived human pancreatic tumor xenografts" reviewed the identification of a distinct three-gene signature as a predictive biomarker for response to vantictumab combined with gemcitabine plus Abraxane. The three-gene biomarker has been validated in multiple patient-derived xenograft models and is now being utilized in an ongoing Phase 1b study of vantictumab in combination with standard-of-care therapy in patients with previously untreated Stage IV pancreatic cancer.

"Whenever possible, we strive to identify and validate possible predictive biomarkers that may be able to serve as companion diagnostics early on in the clinical development process. We are optimistic about the correlation observed between RSPO3 gene expression and anti-RSPO3’s efficacy and have begun using these assays in our ongoing Phase 1a/1b clinical trial," said Ann Kapoun, PhD, Vice President, Translational Medicine. "Vantictumab is another candidate that has proven amenable to the identification of predictive biomarkers. In addition to the three-gene pancreatic assay now being utilized in our Phase 1b clinical trial, last year we presented data on a six-gene biomarker for breast cancer, which is also now being assessed in the clinic. Data from our ongoing clinical trials of anti-RSPO3 and vantictumab are anticipated later in 2016."

Anti-DLL4 was evaluated in a series of NSCLC patient-derived xenografts to model demcizumab treatment in humans as a single-agent and in combination with standard-of-care carboplatin/pemetrexed. Data presented detailed anti-DLL4’s multi-pronged mechanism of action. Notch pathway and stem-cell related genes were down-regulated and a decrease in tumor-initiating cells was observed in anti-DLL4-treated tumors. Evidence of anti-DLL4’s vascular mechanism of action was affirmed by observations of up-regulation of endothelial-related genes, increases in blood vessel density and modification of hypoxia-related gene expression. Studies in humanized mice, created by engraftment of human hematopoietic stem cells with patient-derived xenograft tumors allowed researchers to observe an increase anti-DLL4’s immune activity in the presence of human lymphocytes, including up-regulation of human CD45+ cells and down-regulation of human CD33+ cells in tumors. Anti-DLL4 showed tumor growth inhibition and the combination with chemotherapy demonstrated improved activity. These findings provide additional evidence supporting demcizumab as a potential treatment for NSCLC. Data were presented in Abstract 4652: "Effects of anti-DLL4 treatment on non-small cell lung cancer (NSCLC) human xenograft tumors". A Phase 2 trial (DENALI) testing demcizumab in combination with chemotherapy is currently enrolling.

On April 20, 2016 Acetylon Pharmaceuticals, Inc., the leader in the development of selective histone deacetylase (HDAC) inhibitors for enhanced therapeutic outcomes, reported the presentation of data demonstrating that selective HDAC6 inhibition results in dosedependent increases in cell killing as a single treatment and in combination with Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (Imbruvica), in patient-derived cell lines and preclinical models of chronic lymphocytic leukemia (CLL) (Press release, Acetylon, APR 20, 2016, View Source [SID:1234511168]). The studies were completed in collaboration with the laboratory of Javier Pinilla-Ibarz, M.D., Ph.D. at the Moffitt Cancer Center and the data were presented by Moffitt investigator, Eva Sahakian, Ph.D., in a poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans.

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In CLL, malignant B cells evade immune detection and lead to immune suppression. Recently, histone deacetylases (HDACs) have been shown to play an active role in the regulation of pathogenesis and immune-related pathways in CLL, although their role in B-cell receptor signaling remains unknown. Previously, aberrant overexpression of HDAC6 has been demonstrated in CLL cell lines and patient samples, and the authors sought to understand the mechanistic role of HDAC6 in CLL.

In collaboration with Acetylon scientists, the authors demonstrated that selective HDAC6 inhibition in CLL cell lines resulted in dose-dependent reductions in IL-10, a cytokine that regulates cell proliferation in CLL, as well as dose-dependent increases in cell death and a synergistic reduction in cell viability in combination with the BTK inhibitor, ibrutinib. Genetic knockdown of HDAC6 in CLL cells reduced expression of PD-L1 and other immune checkpoint markers, while increasing markers related to antigen presentation, including MHC II. Using an animal model of CLL, the authors then demonstrated with systemic administration of a selective HDAC6 inhibitor, a reduction in disease burden and increased survival in parallel with diminished expression of immune checkpoint markers on T-cells and B-cells, as well as a reduction in the number of immunosuppressive T-cells (Tregs).

"The preclinical findings presented at AACR (Free AACR Whitepaper) today demonstrate that selective HDAC6 inhibition may provide a successful combination immunotherapeutic strategy for the treatment of CLL," said Steven Quayle, Ph.D., Senior Scientist at Acetylon.
"Overall these data further support the broad versatility and immunomodulatory capability of our selective HDAC6 inhibitors in multiple drug combinations across a breadth of oncology applications, including hematologic as well as solid tumor indications," said Simon S. Jones, Ph.D., Senior Vice President, Head of Research and Preclinical Development at Acetylon.

Details of the presentation are as follows:

Date: Wednesday, April 20, 2016
Time: 7:30 AM -11:00 AM CDT
Location: Section 4
Session: Epigenetic Biomarkers and Therapies
Poster Board Number: 29
Abstract Number: 4485
Title: Regulation of chronic lymphocytic leukemia (CLL) immunobiology by histone deacetylase 6 (HDAC6)

About HDAC6 Inhibition
Ricolinostat (ACY-1215) and ACY-241 selectively inhibit the intracellular enzyme HDAC6, which leads to an accumulation of excess protein and in addition may disrupt critical proliferative signals in malignant cells. Disruption of these molecular processes in cancer cells triggers programmed cell death, called "apoptosis," with little or no effect on normal cells. Currently available HDAC drugs also affect the expression of numerous other genes in normal cells as well as cancer cells, which can result in side effects such as gastrointestinal dysfunction, lowered blood platelet levels and risk of hemorrhage and profound fatigue as well as potential for significant cardiac toxicity. Selective inhibition of HDAC6 is expected to reduce or eliminate these often-severe side effects associated with non-selective HDAC inhibition and may enable the development of optimized treatment regimens, including maximally effective combination drug therapies.