On February 20, 2020 Yale Cancer Center researchers, reported that even a tiny amount of a biomarker known as PD-L1 (programmed death-ligand1) can predict a long-term survival benefit from using pembrolizumab (Keytruda) (Press release, Yale University, FEB 20, 2020, View Source [SID1234554554]). The drug is one of the first checkpoint inhibitors to be developed and used in cancer treatment. The findings are published online today in the Journal of Clinical Oncology.

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"The response that we have seen from pembrolizumab, in a subset of patients years after treatment ended, is remarkable, especially since their chemotherapy had initially failed," said Roy S. Herbst, M.D., Ph.D., chief of Medical Oncology at Yale Cancer Center and Smilow Cancer Hospital and Associate Cancer Center Director for Translational Research at Yale Cancer Center.

The findings come from the phase III KEYNOTE-010 clinical trial, which was conducted in 202 academic medical centers in 24 countries. The study enrolled patients who had previously been treated unsuccessfully with chemotherapy for stage 3 or 4 non-small cell lung cancer (NSCLC), the most common type of lung cancer. The study compared use of pembrolizumab in 690 patients to treatment of docetaxel chemotherapy in 343 patients. In the 79 of 690 patients who received two years of pembrolizumab, overall survival was about 99% one year after discontinuing treatment. Overall, survival in this group three years after the two-year treatment period ranged from 23% to 35%, depending on how much of the PD-L1 biomarker their cancer expressed, compared with 11% to 13% in patients receiving chemotherapy.

Even more surprising, Herbst added, is that some patients whose cancer recurred after an initial two years of treatment responded to pembrolizumab when the drug was offered again.

"Before we had pembrolizumab, survival from advanced lung cancer was measured in months, not years," Herbst said. "It is too soon to say that pembrolizumab is a potential cure for a substantial number of patients whose tumors express PD-L1, and we know that it doesn’t work for all patients, but, the agent remains very, very promising. The majority of patients who completed two years of treatment remain in remission and those who had recurrence could be retreated with pembrolizumab at the time of progression and still achieve disease control."

The PD-L1 designation refers to the PD-1 pathway that cancer uses to hide from killer immune cells. Switching on this pathway stops these immune cells from attacking cancer cells, allowing tumors to grow and spread. Checkpoint inhibitors either block the PDL-1 protein that is expressed on the outside of tumor cells, or the PD molecule on immune cells. Pembrolizumab blocks PDL-1, freeing immune cells to target the cancer.

Investigators estimate that 75% of NSCLC patients express PD-L1 protein on their cancer cells, and within this group, up to 25% express a high amount. The rest express a lower quantity. The percentage of expression is quantified by a tumor proportion score (TPS) that "pulls" about 100 cancer cells from a tumor and counts the number of cells that express PD-L1. The amount is then described as either cancer that expresses more than 50% PD-L1 or more (TPS ?50) or 1 percent PD-L1 or more (?1).

Pembrolizumab is the first checkpoint inhibitor to test the ability of a biomarker to help determine disease control outcomes, and that biomarker has now been tested for the longest period of any clinical trial. "Currently, the agent is being used in all potential settings," Herbst added, "before any other treatment, after other treatment, and with other treatments."

"Our hope is to find the very best way to use pembrolizumab to treat individual lung cancer patients, assessing how much PD-L1 a tumor expresses, what stage the patient is in, as well as other variables and biomarkers we are working on," Herbst said. "This is the story of tailored therapy."

On February 20, 2020 NanoString Technologies, Inc. (NASDAQ:NSTG), a leading provider of life science tools for discovery and translational research, reported ten scientific studies utilizing the GeoMx Digital Spatial Profiler (DSP) that will be showcased at the 2020 Advances in the Genome Biology and Technology (AGBT) conference being held at the JW Marriott in Marco Island, Florida (Press release, NanoString Technologies, FEB 20, 2020, View Source [SID1234554572]). These studies span cancer translational research to neuroscience discovery applications, illustrating the platform’s flexibility and opportunity to spatially map distinct cell types and quantitate biological activity. NanoString will also be hosting the 2nd Annual Spatial Genomics Summit on Sunday, February 23rd from 12 – 4pm ET. Attendees do not need to be registered for AGBT to attend the Summit.

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The GeoMx Digital Spatial Profiler provides researchers high throughput, high multi-plex, spatial profiling of RNA and protein targets in a variety of sample types, including both fresh frozen and formalin-fixed, paraffin-embedded (FFPE) tissue sections. GeoMx DSP is currently available for read-out using NanoString’s nCounter Analysis System, allowing analysis of up to 96 proteins and 96 RNA targets. Beginning mid-2020, GeoMx DSP will be enabled to read-out on Illumina’s Next Generation Sequencers (NGS), which will increase the number of RNA targets that can be analyze by approximately twenty-fold. First NGS-enabled assay will be Cancer Transcriptome Atlas for human samples, which profiles more than 1,800 genes within oncology and immune pathways. This will be followed in 2021 with launch of the Whole Transcriptome Atlases for human and mouse.

"As one of the first labs in the world to have acquired the GeoMx DSP platform, we are enthusiastic about the potential to discover novel biology with the system," said Alex Swarbrick Ph.D., Garvan Institute of Medical Research, Sydney, Australia. "We used the GeoMx Whole Transcriptome Atlas to spatially characterize distinct cell types in triple negative breast cancer. These data allowed us to track the spatial heterogeneity of cancer signaling pathways and of T cell subsets, leading to insights inaccessible to bulk or single-cell RNA sequencing."

"2020 is shaping up to be the breakthrough year for spatial biology," said Brad Gray, president and CEO of NanoString. "At the AGBT conference, researchers will highlight the powerful new capabilities that will be unlocked using NGS read-out, including our Cancer Transcriptome and Whole Transcriptome Atlases. I’d like to thank all of our customers and collaborators that have worked so diligently to make such groundbreaking research a reality."

At AGBT 2020, studies performed by leading academic researcher centers demonstrate three major applications for GeoMx DSP:

Discovering novel spatial biomarkers that are not readily detectable by traditional bulk profiling

Spatial landscape of the immune microenvironment in metastatic prostate cancer using GeoMx Digital Spatial Profiler
Pete Nelson, MD, et al., Fred Hutchinson Cancer Research Center, Seattle, WA USA
Used GeoMx DSP Cancer Transcriptome Atlas to interrogate tissue microarrays of metastatic prostate cancer samples and characterize immune responses. Spatial analysis revealed intra-patient heterogeneity that would not have been readily apparent from bulk RNA profiling experiments.

Spatial proteomic characterization of the tumor and immune microenvironment reveals features associated with response to neoadjuvant HER2-targeted therapy
Katherine McNamara et al., Stanford University, Palo Alto, CA, USA
Used spatial proteomic analysis of biopsies from on-treatment HER2+ breast cancer patients to stratify responders v. non-responders early during a course of neoadjuvant HER2-targeted therapy. GeoMx analysis allowed unique segmentation of cell populations to provide insight into the effect of innate immune markers, ER status, and PAM50 subtype on treatment response.

Identification of cell type-specific RNA biomarker candidates in melanocytic tumors using GeoMx Digital Spatial Profiling
Maija Kiuru, MD, Ph.D., University of California, Davis, CA, USA
GeoMx Cancer Transcriptome Atlas analysis revealed microenvironment-specific expression of a novel cell-type specific biomarker, DAMP, in response to early melanoma development. This marker may allow for more sensitive detection of melanoma via patch biopsy.

Single-nucleus RNA-seq reveals distinct intratumoral transcriptomic heterogeneity in treatment-naïve and chemoradiotherapy-treated primary pancreatic ductal adenocarcinoma
William Hwang, MD, Ph.D., et al. et al., Broad Institute, Cambridge, MA, USA
GeoMx Cancer Transcriptome Atlas and Whole Transcriptome Atlas applications were used to profile tumor, fibroblast, and immune compartments in Pancreatic ductal adenocarcinoma (PDAC) samples from twelve patients. Differential gene expression was measured in tumor and fibroblast compartments between treatment groups and by levels of immune infiltration.

Spatial Profiling of the Immune Landscape of Solid Tumors Treated with Low Dose Radiation and Immunotherapy Using High Plex RNA Profiling with the GeoMx Platform
Krisztian Homicsko, MD, Ph.D., et al., Ludwig Institute for Cancer Research, Lausanne, Switzerland
This project interrogated gene expression changes associated with low-dose radiation immunogenic induction therapy in ovarian cancer. GeoMx Cancer Transcriptome Atlas analysis revealed a pretreatment microenvironment associated with favorable response to therapy, and allowed in depth analysis of needle core biopsies, providing important spatial information in samples that would not have been ideal for bulk transcriptomic assays.

Localizing and quantifying the immune contexture of human glioma with GeoMx high -plex RNA profiling
Troy McEachron, MD, et al., University of Southern California, Los Angeles, CA, USA
Combined single cell RNA sequencing with GeoMx Cancer Transcriptome Atlas analysis to characterize immune cell distribution in glioma samples. GeoMx DSP demonstrates that synchronizing digital pathology and bioinformatics provides layers of insight that conventional methods couldn’t.

Spatial mapping of the whole transcriptome in FFPE tissue

Neural stem cell differentiation trajectories in the developing human brain revealed by whole-transcriptome in situ spatial profiling
Kenny Roberts, MD, Ph.D., et al. et al., Sanger Institute, Cambridge, UK
GeoMx DSP Whole Transcriptome Atlas was used to distinguish the transcriptomic profiles of neural stem cells, intermediate progenitors and neurons in the fetal human cerebral cortex at 14 and 19 post-conception weeks. This study examined cell type specific gene expression programs throughout the cortical germinal zones, subplate and the maturing cortical plate and identified spatiotemporal gene expression correlated with neural stem cell self-renewal and differentiation.

Single Cell Programs of Immune Activation in Human MSI vs MSS Colorectal Carcinoma
Jonathan Chen, MD, Ph.D., et al. et al., Broad Institute, Cambridge, MA, USA
GeoMx DSP Cancer Transcriptome Atlas and Whole Transcriptome Atlas were used to interrogate how tumor and microenvironment interactions vary spatially within colorectal cancers, allowing spatial mapping of signatures linked to single cell RNA sequencing. This study highlights the capacity of GeoMx to identify locations of specific cell populations distributed across tissues.

Measuring the Spatial Whole Transcriptome and High-Plex Proteins on FFPE samples from Glioblastoma Multiforme Immunotherapy Clinical Trials Using Digital Spatial Profiling

Yue Lu Ph.D., et al., Institute Systems Biology, Seattle, WA, USA
GeoMx Cancer Transcriptome Atlas analysis of glioblastoma multiforme (GBM) samples generated a high-resolution spatial map of the tumor microenvironment and provided the framework for creating a GBM tumor atlas. Use of whole transcriptome sequencing combined with spatial analysis provides the potential to discover the biology underpinning response to new immunotherapy treatment for glioblastoma.

Phenotyping of single cells through spatial profiling algorithms

Mapping intratumoural heterogeneity of triple negative breast cancer through integrated single cell RNA-Sequencing and whole transcriptome Digital Spatial Profiling
Alex Swarbrick Ph.D. et al., Garvan Institute of Medical Research, Sydney, Australia
Primary, untreated, triple negative breast cancer (TNBC) was profiled using GeoMx DSP whole transcriptome. Segmentation was performed based on visual markers characterize immune and stromal cells in the invasive edge, tumor core, and distant stromal regions with the goal of discovering novel therapeutic targets in TNBC.

Updating immune cell deconvolution for the spatial genomics era
Danaher Ph.D. et al., NanoString Technologies, Seattle, WA USA
GeoMx DSP Cancer Transcriptome Atlas was used to estimate abundance of different immune cell types using novel computational methods. This allows researchers to study how immune cells interact spatially in different regions of a tissue.

Enabling pathway analysis of RNA expression in formalin-fixed paraffin embedded tissues with the GeoMx DSP Platform.
Boykin et al., NanoString Technologies, Seattle, WA USA
GeoMx Cancer Transcriptome Atlas, bulk RNA sequencing, and NanoString nCounter analysis was used to profile the same samples. This project demonstrates how GeoMx analysis can be expanded beyond single gene analysis to understand how biological pathways vary spatially in different regions of a tissue.

NanoString is currently accepting applications to a Technology Access Program for its Cancer Transcriptome Atlas using the DSP technology at [email protected].

To learn more about GeoMx DSP, please visit View Source

On February 20, 2020 Biocare Medical, a leading provider of innovative, automated immunohistochemistry (IHC) reagents and instrumentation, reported the launch of seven novel IVD IHC antibody markers for clinical diagnostics and research applications (Press release, Biocare Medical, FEB 20, 2020, View Source [SID1234554588]). The most recent launch focuses on several immuno-oncology markers, critical in aiding early-stage cancer drug developments and patient treatment.

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Biocare re-developed a major antibody marker (S100 Protein), which is expressed in Schwannomas, ependymomas, astrogliomas, and nearly all melanomas (benign and malignant) and their metastases. Biocare’s new marker, S100 [4C4.9], lends a stronger and more robust staining signal for IHC applications vs. previous offerings.

Biocare also releases one mouse monoclonal and five novel rabbit monoclonal antibodies in the immuno-oncology space. Recombinant rabbit monoclonal antibodies are ideal for research applications for use with Multiplex IHC technologies and are not reliant upon hybridomas that may expire. CTLA-4 [CAL49], GITR [CAL8], LAG3 [CAL26], PD-1 [CAL20], CD22 (M) [BLCAM/1796], and E-Cadherin [CDH1/2208R] are now commercially available.

CTLA-4 – Ipilimumab, the first immunotherapeutic drug directed toward CTLA-4 inhibition, has demonstrated overall survival benefit in metastatic melanoma. Another CTLA-4 inhibitor, tremelimumab (IgG2 isotype), has also proven successful in metastatic melanoma and other malignancies1,2.

GITR – GITR modulation in preclinical models has shown promising antitumor activity via significant increase in effector T cells and decrease in Tregs3. Several human monoclonal antibodies that agonize GITR are currently undergoing phase I clinical studies in various solid malignancies. Preliminary results demonstrate an acceptable safety profile without dose limiting toxicities4-5.

LAG3 – Recent studies in a metastatic ovarian cancer mouse model showed that LAG-3 blockade leads to upregulation of other immune checkpoints (PD-1, CTLA4, and TIM-3), and combination therapy targeting LAG-3, PD-1, and CTLA-4 increases functional cytotoxic T cell levels while reducing Tregs and myeloid-derived suppressor cells6,7.

PD-1 – Treatments targeting PD-1 and its ligand, PD-L1, have also shown encouraging results in melanoma, non-small-cell lung cancer, and renal cell carcinoma8-10. This antibody can also be used in multiplex stains with other antibodies such as CD4, CD8, FOXP3, cytokeratin, and melanoma markers11.

CD22 (M) – May be a useful marker for phenotyping mature leukemias, as CD22 membrane expression has been shown to be limited to the late differentiation stages between mature B cells (CD22+) and plasma cells (CD22-)12, 13. CD22 is also strongly expressed in hairy cell leukemia14.

E-cadherin – A decreased expression of E-cadherin is associated with metastatic potential and poor prognosis in breast cancer, prostate, and esophageal cancer.

"We are proud to be able to launch novel, IVD IHC markers that meet the highest standards in cancer diagnostics. This commitment to quality ensures Biocare is providing the best diagnostic and research utility possible," said Dr. Jason Ramos, Vice President – Reagent Research and Development at Biocare Medical.

The new product launches continue Biocare Medical’s long-standing history of providing novel, high-quality reagents to customers looking to advance their research and diagnostic efficiency in the laboratory.

On February 20, 2020 Kyowa Kirin Co., Ltd. (TSE: 4151, President and CEO: Masashi Miyamoto, "Kyowa Kirin") reported that a phase 1 clinical study of automated injection device of G-Lasta [KRN125, generic name: pegfilgrastim (genetical recombination)] *1 was started in Japan, February 19, 2020 (Press release, Kyowa Hakko Kirin, FEB 20, 2020, View Source [SID1234554536]).

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G-Lasta is a sustained duration form of Granulocyte Colony-Stimulating Factor (G-CSF) product*2. It was licensed from Kirin-Amgen Inc.*3 to Kyowa Kirin, and launched in Japan in 2014 for decreasing the incidence of febrile neutropenia*4 in patients receiving cancer chemotherapy. It is administered at medical institutions at least one day after chemotherapy. This automated injection device has a function to deliver G-Lasta into patient’s body the day after chemotherapy, and is applied to patients on the same day of chemotherapy. Therefore, it is expected to reduce the ambulant burden on patients, and contributes to reducing burden on healthcare professionals.

"Burden on patient’s body is heavy after chemotherapy, and it is very important to reduce it." said Takeyoshi Yamashita, Ph.D., Executive officer, Director of Corporate Strategy & Planning Department of Kyowa Kirin. "We believe that this device contributes to reducing the burden on patients." Kyowa Kirin will file an application for manufacturing and marketing approval with Japan’s Ministry of Health, Labor and Welfare (MHLW) using this phase 1 clinical study’s data which is objected to evaluate safety of G-Lasta. This device is co-developed with a domestic medical equipment manufacturer.

The Kyowa Kirin Group companies strive to contribute to the health and well-being of people around the world by creating new value through the pursuit of advances in life sciences and technologies.

Indication Decrease the incidence of febrile neutropenia in patients receiving cancer chemotherapy
Phase Phase 1
Design Multicenter open-label single-arm study
Administration group KRN125 group
Primary evaluation items Safety
Sample size 30
Countries Japan *1:

About G-Lasta
G-Lasta is a sustained duration form of Granulocyte Colony-Stimulating Factor (G-CSF) product, which is produced by PEGylation*5 of filgrastim, for decreasing the incidence of febrile neutropenia in patients receiving cancer chemotherapy. Pegfilgrastim, originally generated by Amgen, Inc., was licensed from Kirin-Amgen Inc., to Kyowa Kirin. *

2: About Granulocyte Colony-Stimulating Factor (G-CSF) product G-CSF is a protein produced by using gene recombination. G-CSF selectively stimulates production of neutrophils and also enhances the neutrophil function. Based on this mechanism, G-CSF is used to accelerate recovery from chemotherapy-induced neutropenia, and it reduces various risks associated with neutropenia. *

3: About Kirin-Amgen Inc. At the time of its licensing, it was a joint venture between Amgen and Kirin Holdings. In 2017, they have agreed to terminate the joint venture. And it is now a subsidiary of Amgen. *

4: About febrile neutropenia Myelosuppressive chemotherapy causes low neutrophil count, i.e. neutropenia, which can raise risk of infections. Neutropenia with fever, known as febrile neutropenia, can be a sign of a serious infection and the patient needs to be given appropriate treatments. *

5: About PEGylation PEGylation is a chemical modification of protein bound by polyethylene glycol. PEGylation enables protein to suppress degradation and to reduce clearance in human body, resulting in improving retention of the protein in the blood stream and prolonging the duration of its activities.

On February 20, 2020 The board of directors of AbbVie Inc. (NYSE: ABBV) reported a quarterly cash dividend of $1.18 per share (Press release, AbbVie, FEB 20, 2020, View Source [SID1234554555]).

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The cash dividend is payable May 15, 2020 to stockholders of record at the close of business on April 15, 2020.

Since the company’s inception in 2013, AbbVie has increased its dividend by 195 percent. AbbVie is a member of the S&P Dividend Aristocrats Index, which tracks companies that have annually increased their dividend for at least 25 consecutive years.