On April 3, 2017 NanoString Technologies, Inc. (NASDAQ:NSTG), a provider of life science tools for translational research and molecular diagnostic products, reported the validation of its novel Digital Spatial Profiling (DSP) technology by the current state-of-the-art AQUA method for quantitating protein targets in FFPE (Press release, NanoString Technologies, APR 3, 2017, View Source [SID1234518420]). The data was generated through a collaboration between NanoString and Dr. David Rimm’s lab at the Yale School of Medicine as part of a Technology Access Program for NanoString’s DSP technology. The data will be presented in a poster session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) conference, being held April 1-5, 2017 in Washington, D.C.

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"We are excited to be working with NanoString on their new Digital Spatial Profiling technology. Our AQUA quantitative fluorescence approach has been limited to 4-5 fold multiplexing, where DSP can currently multiplex up to 50 protein analytes and has the potential to measure hundreds of RNAs simultaneously on the same tissue section," said Dr. David L. Rimm, Professor of Pathology and of Medicine (Medical Oncology); Director of Pathology Tissue Services; Director of Translational Pathology, Yale University. "This brings many advantages, including the ability to include ‘housekeeping’ proteins for standardization of assays and normalization of pre-analytic variables. Because of the variable sized sample region, it is a perfect match for the ‘field of view’ assessment we do with the AQUA technology in our lab. We designed AQUA to measure at the molecular level rather than the cellular level, and the same is true of NanoString’s DSP."

AQUA technology, which was developed by Dr. Rimm, has been demonstrated to be both reproducible and quantitative when applied to tissue-based immunoassays. This study demonstrated that both DSP and AQUA are quantitative methods for profiling protein expression, eliminating the subjectivity and variability associated with conventional immunohistochemistry techniques. However, benchmarking against AQUA revealed several key advantages of DSP technology, including the high multiplex capability and wide dynamic range. These capabilities are of particular significance when profiling tumor cell specific protein expression from the complex tumor microenvironment.

"Localized expression of immuno-regulatory proteins shapes the immune response against tumors, and the detection of cell specific proteins can reveal the presence of important immune cell populations," stated Alessandra Cesano, M.D., Ph.D, chief medical officer at NanoString. "Spatial profiling of these key molecules could lead to discovery of novel therapeutic targets and signatures that characterize immunological responses. This could enable predictive biomarkers to guide the development of immunotherapies and companion diagnostics."

Digital Spatial Profiling will be featured in two additional posters and a spotlight presentation during the AACR (Free AACR Whitepaper) meeting. Merritt et al., will present recent technical advances of the platform including single cell selection and RNA profiling. Balko et al., applied the technology to characterizing checkpoint inhibitor therapy-induced autoimmune toxicities. The spotlight presentation will feature the inventors of the technology, Dr. Gordon Mills and Dr. Joseph Beechem who will speak about the potential of the platform to enable deep molecular characterization of complex biological phenomenon and provide greater insight into tumor immune cell interactions.

NanoString is accelerating the development of the Digital Spatial Profiling technology with customers via its Technology Access Program. Under the program, customers submit up to 20 FFPE tissue sections and NanoString performs a high-plex protein spatial profiling assay with a panel of 30 pre-validated immuno-oncology targets. An assay report along with raw digital data and processed results are provided back to customers. Researchers interested in participating in NanoString’s technology access program for its Digital Spatial Profiling technology should contact the company at [email protected].

Key DSP Events at AACR (Free AACR Whitepaper) 2017

Spotlight Presentation: Monday, April 3: 10:00am – 11:00am ET Spotlight Theater B – Hall A
Powering Precision Oncology Research with 3D Biology Technology: High Plex Multi-Analyte Profiling on FFPE with Spatial Resolution.
Gordon B. Mills M.D. Ph.D., Professor and Chair of Systems Biology at MD Anderson Cancer Center and Joseph M. Beechem, PhD, Senior Vice President of Research & Development, NanoString Technologies.

Poster # 3810 – Tuesday, April 4: 8:00am – 12:00pm ET
Validation of novel high-plex protein spatial profiling quantitation based on NanoString’s Digital Spatial Profiling (DSP) technology with quantitative fluorescence (QIF) [Section #32, Board #6]
Maria I. Toki, M.D., Ph.D., Yale School of Medicine

Poster # 588 – Sunday, April 2: 1:00 PM-5:00 PM
Advanced molecular characterization of severe autoimmune toxicities associated with checkpoint inhibitor therapies [Section #25, Board #22]
Justin M. Balko, Pharm.D., Ph.D., Assistant Professor of Cancer Biology, Vanderbilt University

Poster# 3955 – Tuesday, April 4: 8:00 AM-12:00 PM
Spatially resolved, multiplexed digital characterization of protein and mRNA distribution and abundance in formalin-fixed, paraffin-embedded (FFPE) tissue sections based on NanoString’s Digital Spatial Profiling [Section #41, Board #22]
Chris Merritt, Ph.D., NanoString Technologies

On April 3, 2017 Intrexon Corporation (NYSE: XON), a leader in the engineering and industrialization of biology to improve the quality of life and health of the planet, ZIOPHARM Oncology (NASDAQ: ZIOP), a biopharmaceutical company focused on new immunotherapies, and Merck KGaA, Darmstadt, Germany, a leading science and technology company, reported an update on the development of next-generation chimeric antigen receptor T cell (CAR-T) therapy for cancer as part of their strategic collaboration and license agreement (Press release, Intrexon, APR 3, 2017, View Source [SID1234518419]).

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Intrexon and ZIOPHARM Oncology, in an exclusive partnership with Merck KGaA, Darmstadt, Germany, are advancing a unique approach to develop therapeutic candidates for two CAR-T targets expressed on a wide range of tumor types, including hematologic malignancies and solid tumors.

The distinctive methodology centers on two technologies: the proprietary RheoSwitch Therapeutic System (RTS) platform to regulate expression of membrane-bound interleukin-15 (mbIL15) co-expressed with CARs and Sleeping Beauty non-viral gene integration.

"Sleeping Beauty and the RTS approach are a powerful combination to improve the manufacturing process and instill control over CAR-modified T cells co-expressing cytokines such as membrane-bound IL-15. The collaboration with Intrexon and Merck KGaA, Darmstadt, Germany, has been a catalyst to progress these next-generation gene therapy technologies. We are excited by the progress and look forward to advancing this innovative approach toward the clinic in mid-2018," said Laurence Cooper, M.D., Ph.D., Chief Executive Officer of ZIOPHARM.

The interleukin-15 (IL-15) cytokine is increasingly recognized as a key driver of therapeutic effect in CAR-T therapy, including in a recent Journal of Clinical Oncology publication which correlated lymphoma remissions with elevated IL-15 levels. Through the RTS gene switch, the expression of mbIL15 can be regulated to help CARs target cancers in a controlled manner, thus providing a new paradigm in T-cell therapy.

Additionally, the non-viral Sleeping Beauty transposon-transposase is an exceptional system for introducing genes encoding CARs and TCRs into T cells that holds multiple advantages over viral-based delivery systems. It simplifies genetic modification, and when coupled with reduced ex vivo processing, offers a pathway to shortened manufacturing and personalized T-cell therapies.

On April 3, 2017 Halozyme Therapeutics, Inc. (NASDAQ: HALO), a biotechnology company developing novel oncology and drug-delivery therapies, reported in preclinical models that its investigational drug PEGPH20 increases the number of cancer-fighting white blood cells accumulating in the tumor and the effectiveness of immunotherapies (Press release, Halozyme, APR 3, 2017, View Source [SID1234518418]). The research was presented at the 108th annual meeting of the American Association of Cancer Research (AACR) (Free AACR Whitepaper) and builds upon prior preclinical findings.

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"We are encouraged that these findings from our animal models continue to support the potential benefits of remodeling the tumor microenvironment in stimulating an immune response and improving the efficacy of checkpoint inhibitors and cell-based immunotherapies," said Dr. Helen Torley, president and CEO. "We are pleased that PEGPH20 continues to demonstrate significantly improved tumor growth inhibition in certain hard-to-treat hyaluronan-rich cancer models when administered in combination with additional cancer fighting agents."

PEGPH20 is a proprietary enzyme that targets and degrades hyaluronan (HA), a glycosaminoglycan or naturally occurring sugar in the body. HA accumulates in higher concentrations around many solid tumors, potentially constricting blood vessels, impeding the immune response and the access of other therapies.

Research to be presented includes data from a breast cancer mouse model treated with PEGPH20 which showed a significant increase in the accumulation of cancer-fighting CD8+ T cells, also called tumor infiltrating lymphocytes (TILs), compared to mice untreated with PEGPH20. Additional research shows that PEGPH20 administered in combination with an anti-PD-L1 immune checkpoint inhibitor and with Aduro’s Listeria-based vaccine immunotherapy facilitated CD8+ T-cell accumulation and improved effectiveness over what was achieved with either the anti-PD-L1 or Listeria immunotherapy alone.

PEGPH20 increased the anti-PD-L1 effectiveness by 411 percent compared to anti-PD-L1 alone as measured by tumor growth inhibition (93% vs 18.2%, p<0.0001) and increased the accumulation of CD8+ T cells by 176 percent (p=0.0025) in an HA-rich mouse model. Taken together, these data suggest that tumor HA accumulation may act as a barrier to immune cell access and that PEGPH20-mediated HA reduction facilitates increased access of CD8+ T cells.

Halozyme and other researchers are conducting further investigations to determine the potential of combining PEGPH20 with adoptive T cell and other immunotherapies. Halozyme has ongoing clinical studies of PEGPH20 in combination with chemotherapy and immunotherapies, with plans to initiate new studies in a previously announced clinical collaboration with Genentech combining PEGPH20 with atezolizumab, an anti-PD-L1 therapy, in up to eight tumor types.

Halozyme’s AACR (Free AACR Whitepaper) abstracts include:

PEGylated recombinant hyaluronidase PH20 (PEGPH20) enhances tumor infiltrating CD8+ T-cell accumulation and improves checkpoint inhibitor efficacy in murine syngeneic breast cancer models. Abstract 641. Sunday, April 2, 1 to 5 p.m. ET

HTI-1511, a novel anti-EGFR-ADC, overcomes mutation resistance and demonstrates significant activity against multiple tumor types in preclinical studies. Abstract 50. Sunday, April 2, 1 to 5 p.m. ET

Evaluating clinically relevant pharmacological agents in a rat ambulation model to ameliorate PEGylated recombinant hyaluronidase PH20 (PEGPH20)-mediated musculoskeletal adverse events. Abstract 1240. Monday, April 3, 8 a.m. to noon ET

A Phase 1b study of PEGPH20 plus pembrolizumab in patients with selected hyaluronan-high solid tumors. Abstract CT032. Monday, April 3, 8 a.m. to noon ET.

Global phase 3, randomized, double-blind, placebo-controlled study evaluating PEGylated recombinant human hyaluronidase PH20 (PEGPH20) plus nab-paclitaxel and gemcitabine in patients with previously untreated, hyaluronan (HA)-high, stage IV pancreatic ductal adenocarcinoma. Abstract CT066. Monday, April 3, 1 to 5 p.m. ET

Combination of PEGylated recombinant hyaluronidase PH20 (PEGPH20) with Live-attenuated, Double-Deleted (LADD) Listeria enhances tumor infiltrating
CD8+ T cell response and antitumor efficacy in mice. Abstract LB-198. Tuesday, April 4, 8 a.m. to noon ET

PEGylated adenosine deaminase 2 (PEG-ADA2) abrogates the cytoprotective effects of adenosine against chronic lymphocytic leukemia cells. Abstract 5583. Wednesday, April 5, 8 a.m. to noon ET

About PEGPH20

PEGPH20 is an investigational PEGylated form of Halozyme’s proprietary recombinant human hyaluronidase under clinical development for the potential systemic treatment of tumors that accumulate hyaluronan. PEGPH20 is an enzyme that temporarily degrades HA, a dense component of the tumor microenvironment that can accumulate in higher concentrations around certain cancer cells, potentially constricting blood vessels and impeding the access of other therapies. In January, Halozyme announced the positive topline results as of December 2016 of its randomized phase 2 HALO-202 study of PEGPH20 in combination with ABRAXANE (nab-paclitaxel) and gemcitabine chemotherapy in metastatic pancreatic cancer. In the study, PEGPH20 met key endpoints, including in the targeted HA-High patient population.

FDA granted orphan drug designation to PEGPH20 for treatment of pancreas cancer and fast track for PEGPH20 in combination with gemcitabine and nab-paclitaxel for the treatment of metastatic pancreas cancer. Additionally, the European Commission, acting on the recommendation from the Committee for Orphan Medicinal Products of the European Medicines Agency, designated investigational drug PEGPH20 an orphan medicinal product for the treatment of pancreas cancer.

On April 3, 2017 BioCryst Pharmaceuticals, Inc. (NASDAQ:BCRX) reported that Mundipharma has obtained regulatory approval of Mundesine (Forodesine hydrochloride) for the treatment of relapsed/refractory PTCL (Peripheral T-Cell Lymphoma) by the Ministry of Health, Labor and Welfare in Japan (Press release, BioCryst Pharmaceuticalsa, APR 3, 2017, View Source [SID1234518417]). Mundesine is a Purine-nucleoside phosphorylase (PNP) inhibitor developed by BioCryst, under an exclusive license with Albert Einstein College of Medicine and Victoria Link Limited. The Ministry’s decision follows successful clinical trials and makes Japan the first country in the world to make Mundesine available for treatment of PTCL.

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In 2006, BioCryst entered into an exclusive sub-licensing agreement with Mundipharma for the development and commercialization of forodesine in the field of oncology. This agreement was amended and restated in 2011. As stated in their press release, Mundipharma is working to ensure that patients in Japan receive access to Mundesine as early as possible, which represents another positive step forward, as they strive to deliver more treatment options for cancer patients in Japan. Under the terms of the agreement with Mundipharma, BioCryst will receive tiered royalties ranging from the mid- to high-single digit percentages of net sales of Mundesine.

About Forodesine

Forodesine hydrocloride is an orally-available transition-state analog inhibitor of purine nucleoside phosphorylase (PNP), a purine salvage pathway enzyme that is essential for the proliferation of T-cells and B-cells. Typically, T-cells and B-cells are an essential part of the body’s immune system, but when they multiply uncontrollably they can cause various forms of cancer. Inhibiting PNP produces selective suppression of T-cells and B-cells, inducing apoptosis in both types of cells.

On April 3, 2017 AVEO Oncology (NASDAQ:AVEO) reported receipt of a $500,000 milestone payment from CANbridge Life Sciences Ltd., a biopharmaceutical company focused on developing western drug candidates in China and North Asia, related to a technology transfer milestone for AV-203, AVEO’s clinical-stage ErbB3 (HER3) inhibitory antibody candidate (Press release, AVEO, APR 3, 2017, View Source [SID1234518416]). AV-203 has demonstrated preclinical activity in a number of different tumor models including breast, head and neck, lung, ovarian and pancreatic cancers. CANbridge is planning clinical development of AV-203 in squamous cell esophageal cancer as its initial indication.

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"Receipt of this milestone payment from CANbridge reflects continued progress by our partner to engineer the manufacturing process for AV-203 in an effort to develop an antibody manufacturing process suitable for commercialization," said Michael Bailey, president and chief executive officer of AVEO. "We look forward to continued progress in this program, and with the balance of our partnered pipeline, including AV-380, a potentially disease modifying treatment for cachexia which is partnered with Novartis, and ficlatuzumab in development for squamous cell carcinoma of the head and neck and acute myeloid leukemia, which is partnered with Biodesix. With these programs advancing, we continue to focus on tivozanib, including continuing our execution of the TIVO-3 and TiNivo studies for our U.S. pivotal clinical strategy, and support of our licensee, EUSA Pharma, in its response to European regulators."

In March 2016, AVEO announced an exclusive collaboration and license agreement, granting CANbridge worldwide rights to AV-203, excluding the United States, Canada, and Mexico. Under the terms of the collaboration and license agreement, CANbridge paid AVEO an upfront payment of $1 million, and AVEO is also eligible to receive up to $133 million in reimbursement and milestone payments, assuming the successful achievement of specified development, regulatory and commercialization objectives. The transaction was awarded the 2016 Deal of the Year by RNDer, a leading Chinese publication providing value-added analysis for pharmaceutical and biotechnology companies conducting business in China. AVEO has retained North American rights to AV-203 and is also eligible for a tiered royalty, with a percentage range in the low double digits, on net sales of AV-203 in the partnered territories.

AVEO also announced today an update to its financial guidance. The Company believes its recently completed underwritten public offering, which yielded net proceeds of $15.5 million (on gross proceeds of $17.3 million), together with its existing cash resources, would be sufficient to fund its operations into the second quarter of 2018. This guidance excludes any potential partnership milestone payments to or from the Company, potential debt or equity financings, acceleration of existing debt principal payments under the term loan with Hercules which could result from non-compliance with the cash covenant of that agreement, or proceeds from any potential future partnership agreements.

As previously guided, top line data from the TIVO-3 trial, AVEO’s ongoing Phase 3 clinical trial of tivozanib in the third-line treatment of patients with refractory renal cell carcinoma (RCC), is anticipated in the first quarter of 2018.