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New subgroups of ILC immune cells discovered through single-cell RNA sequencing

Reporter: Stephen J Williams, PhD

 

SOURCE

http://ki.se/en/news/new-subgroups-of-ilc-immune-cells-discovered-through-single-cell-rna-sequencing?elqTrackId=f79885cef36049e281109c02da213910&elq=ac700a4d4374478b9d6e10e301ae6b90&elqaid=14707&elqat=1&elqCampaignId=14

Updated on 2016-02-15. Published on 2016-02-15Denna sida på svenska

Jenny Mjösberg and Rickard Sandberg are principal investigators at Karolinska Institutet’s Department of Medicine, Huddinge and Department of Cell and Molecular Biology, respectively. Credit: Stefan Zimmerman.

A relatively newly discovered group of immune cells known as ILCs have been examined in detail in a new study published in the journal Nature Immunology. By analysing the gene expression in individual tonsil cells, scientists at Karolinska Institutet have found three previously unknown subgroups of ILCs, and revealed more about how these cells function in the human body.

Innate lymphoid cells (ILCs) are a group of immune cells that have only relatively recently been discovered in humans. Most of current knowledge about ILCs stems from animal studies of e.g. inflammation or infection in the gastrointestinal tract. There is therefore an urgent need to learn more about these cells in humans.

Previous studies have shown that ILCs are important for maintaining the barrier function of the mucosa, which serves as a first line of defence against microorganisms in the lungs, intestines and elsewhere. However, while there is growing evidence to suggest that ILCs are involved in diseases such as inflammatory bowel disease, asthma and intestinal cancer, basic research still needs to be done to ascertain exactly what part they play.

Two research groups, led by Rickard Sandberg and Jenny Mjösberg, collaborated on a study of ILCs from human tonsils. To date, three main groups of human ILCs are characterized. In this present study, the teams used a novel approach that enabled them to sort individual tonsil cells and measure their expression across thousands of  genes. This way, the researchers managed to categorise hundreds of cells, one by one, to define the types of ILCs found in the human tonsils.

Unique gene expression profiles

Rickard Sandberg, credit: Stefan Zimmerman,

“We used cluster analyses to demonstrate that ILCs congregate into ILC1, ILC2, ILC3 and NK cells, based on their unique gene expression profiles,” says Professor Sandberg at Karolinska Institutet’sDepartment of Cell and Molecular Biology, and the Stockholm branch of Ludwig Cancer Research. “Our analyses also discovered the expression of numerous genes of previously unknown function in ILCs, highlighting that these cells are likely doing more than what we previously knew.”

By analysing the gene expression profiles (or transcriptome) of individual cells, the researchers found that one of the formerly known main groups could be subdivided.

Jenny Mjösberg, credit: Stefan Zimmerman.

“We’ve identified three new subgroups of ILC3s that evince different gene expression patterns and that differ in how they react to signalling molecules and in their ability to secrete proteins,” says Dr Mjösberg at Karolinska Institutet’s Department of Medicine in Huddinge, South Stockholm. “All in all, our study has taught us a lot about this relatively uncharacterised family of cells and our data will serve as an important resource for other researchers.”

The study was financed by grants from a number of bodies, including the Swedish Research Council, the Swedish Cancer Society, the EU Framework Programme for Research and Innovation, the Swedish Society for Medical Research, the Swedish Foundation for Strategic Research and Karolinska Institutet.

Publication

The heterogeneity of human CD127+ innate lymphoid cells revealed by single-cell RNA sequencing
Åsa K. Björklund, Marianne Forkel, Simone Picelli, Viktoria Konya, Jakob Theorell, Danielle Friberg, Rickard Sandberg, Jenny Mjösberg
Nature Immunology, online 15 February 2016, doi:10.1038/ni.3368

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Two New Drugs for Inflammatory Bowel Syndrome Are Giving Patients Hope

Reporter: Stephen J. Williams, Ph.D.

Actavis Receives FDA Approval for VIBERZI (eluxadoline) for the Treatment of Irritable Bowel Syndrome with Diarrhea (IBS-D) in Adults -First in class treatment for IBS-D treats hallmark symptoms of IBS-D; abdominal pain and diarrhea

DUBLIN, May 27, 2015 /PRNewswire/ — Actavis plc (NYSE: ACT) announced today that VIBERZI™ (eluxadoline) was approved by the Food and Drug Administration (FDA) as a twice-daily, oral treatment for adults suffering from irritable bowel syndrome with diarrhea (IBS-D). VIBERZI (eluxadoline) has mixed opioid receptor activity, it is a mu receptor agonist, a delta receptor antagonist, and a kappa receptor agonist.

Logo – http://photos.prnewswire.com/prnh/20130124/NY47381LOGO

“The FDA’s approval of VIBERZI is the first step to providing physicians with a new, evidence-based, treatment option for their adult patients with IBS-D,” said David Nicholson, Executive Vice President, Actavis Global Brands R&D. “At Actavis, we are dedicated to providing new treatment options, and the development of new agents that help address the most bothersome symptoms of IBS-D. We are very pleased to be working with the FDA to advance this IBS-D treatment and we eagerly await DEA scheduling determination later this year.”

IBS-D is a multifactorial disorder marked by recurrent abdominal pain or discomfort and altered bowel function that affects as many as 15 million adult Americans, impacting about twice as many women as men.i,ii,iii There are few treatment options available for IBS-D, particularly options that relieve both the diarrhea and abdominal pain associated with IBS-D.

“The unpredictable symptoms experienced by patients with IBS-D can have a significant impact on everyday life,” said William D. Chey, MD, Nostrant Professor of Gastroenterology at the University of Michigan Health System. “It’s exciting when physicians are able to add an additional treatment option like VIBERZI to their toolbox for patients with IBS-D.”

The FDA has recommended that VIBERZI be classified as a controlled substance. This recommendation has been submitted to the U.S. Drug Enforcement Administration (DEA).  Once VIBERZI receives final scheduling designation, the updated label will be available. Pending final scheduling designation, product launch is anticipated in Q1 2016.

About VIBERZI

VIBERZI is an orally active compound indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in men and women. VIBERZI (eluxadoline) has mixed opioid receptor activity, it is a mu receptor agonist, a delta receptor antagonist, and a kappa receptor agonist.

Efficacy was established in two Phase III clinical studies, demonstrating significant superiority over placebo on the composite endpoint of simultaneous improvement in both abdominal pain and diarrhea at both 75 mg and 100 mg twice daily doses. The primary efficacy responder endpoint was evaluated over the duration of double-blind, placebo-controlled treatment. Response rates were compared based on patients who met the daily composite response criteria (improvement in both abdominal pain and stool consistency on the same day) for at least 50% of the days from weeks 1 to 12 (FDA endpoint) and weeks 1 to 26 (European Medicines Agency endpoint).

The most common adverse events in the two Phase III clinical trials were constipation (7% and 8% for eluxadoline 75 mg and 100 mg; 2% for placebo) and nausea (8% and 7% for eluxadoline 75 mg and 100 mg; 5% for placebo). Rates of severe constipation were less than 1% in patients receiving 75 mg and 100 mg eluxadoline. Rates of discontinuation due to constipation were low for both eluxadoline and placebo (≤2%) and similar rates of constipation occurred between the active and placebo arms beyond 3 months of treatment. A total of 2,426 subjects were enrolled across the two studies.

For more information including full prescribing information about VIBERZI at http://www.actavis.com/Actavis/media/PDFDocuments/VIBERZI_PI.pdf

About IBS-D

Irritable bowel syndrome with diarrhea (IBS-D) is a functional bowel disorder characterized by chronic abdominal pain and frequent diarrhea, which affects approximately 15 million patients in the U.S.  Although the exact cause of IBS-D is not known, symptoms are thought to result from a disturbance in the way the gastrointestinal tract and nervous system interact.

IBS-D can be debilitating and there are limited therapeutic options for managing the chronic symptoms. IBS-D is associated with economic burden in direct medical costs and indirect social costs such as absenteeism and lost productivity, along with decreased quality of life.

About Actavis
Actavis plc (NYSE: ACT), headquartered in Dublin, Ireland, is a unique, global pharmaceutical company and a leader in a new industry model—Growth Pharma. Actavis is focused on developing, manufacturing and commercializing innovative branded pharmaceuticals, high-quality generic and over-the-counter medicines and biologic products for patients around the world.

Actavis markets a portfolio of best-in-class products that provide valuable treatments for the central nervous system, eye care, medical aesthetics, gastroenterology, women’s health, urology, cardiovascular and anti-infective therapeutic categories, and operates the world’s third-largest global generics business, providing patients around the globe with increased access to affordable, high-quality medicines. Actavis is an industry leader in research and development, with one of the broadest development pipelines in the pharmaceutical industry and a leading position in the submission of generic product applications globally.

With commercial operations in approximately 100 countries, Actavis is committed to working with physicians, healthcare providers and patients to deliver innovative and meaningful treatments that help people around the world live longer, healthier lives.

Actavis intends to adopt a new global name – Allergan – pending shareholder approval in 2015.

For more information, visit Actavis’ website at www.actavis.com.

Actavis Cautionary Statement Regarding Forward-Looking Statements

Statements contained in this communication that refer to Actavis’ estimated or anticipated future results, including estimated synergies, or other non-historical facts are forward-looking statements that reflect Actavis’ current perspective of existing trends and information as of the date of this communication. Actual results may differ materially from Actavis’ current expectations depending upon a number of factors affecting Actavis’ business. These factors include, among others, the timing and success of product launches; the difficulty of predicting the timing or outcome of product development efforts and regulatory agency approvals or actions, if any; market acceptance of and continued demand for Actavis’ products; difficulties or delays in manufacturing; and such other risks and uncertainties detailed in Actavis’ periodic public filings with the Securities and Exchange Commission, including but not limited to Actavis plc’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2015 and from time to time in Actavis’ other investor communications. Except as expressly required by law, Actavis disclaims any intent or obligation to update or revise these forward-looking statements.

i Camilleri M. Current and future pharmacological treatments for diarrhea-predominant irritable bowel syndrome. Expert Opinion on Pharmacotherapy. 2013;14:1151.

ii Grundmann O, Yoon SL. Irritable bowel syndrome: epidemiology, diagnosis, and treatment: an update for health-care practitioners. Journal of Gastroenterology and Hepatology. 2010;25:691–699.

iii Eluxadoline Xifaxin Summary Final. November 2014.

CONTACTS:
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(862) 261-7152

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(862) 261-8141

SOURCE Actavis plc

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Synergy’s Looming FDA Filing Makes It Pharma of the Month

By James Passeri Follow

| Jan 05, 2016 | 8:39 AM EST  | 0

Keep an eye on Synergy Pharmaceuticals (SGYP) this month: Analysts like it, its shares have waned since a big spike this summer, and the official filing of its star product is expected any day.

When the New York-based pharmaceutical company, which specializes in gastrointestinal therapy, announced that it passed clinical trials on its flagship drug plecanatide this summer, shares rocketed 95%.

But today analysts appear mystified at why the stock has receded 45% from its July high, especially with plecanatide’s new drug application with the Food and Drug Administration expected this month. (It’s currently trading below $6, and the consensus price target is over $13, according to data provided by Bloomberg.)

Synergy should be raking in $600 million from plecanatide, a daily tablet that treats patients with irritable bowel syndrome (IBS), within five years of obtaining FDA approval (expected in 2017, according to equity research firm BTIG. Synergy currently has a market capitalization of just $645 million.

BTIG’s $11 price target is also buoyed by roughly $142 million on the balance sheet, as well as newly appointed management including CFO Gary Sender and COO Troy Hamilton, both former executives at pharma success story Shire (SHPG). Though Shire shares are down just under 4% over the past 12 month, they have rocketed 112% over the past two years.

Synergy also stands to benefit from a growing demand for gastrointestinal treatments, feeding the appetite of Big Pharma for potential acquisitions, according to BTIG.

“With about 45 million Americans suffering from chronic constipation and IBS, and major companies like Allergan(AGN) and Valeant (VRX) focusing their marketing efforts on GI treatments, it seems logical to imagine SGYP as a takeover candidate,” BTIG analyst Timothy Chiang wrote in a November report.

Whether or not this leads to a buyout or another stock surge, Synergy certainly can be counted on for a healthy dose of small-cap volatility as its chief product takes the final steps toward reaching its customers.

 

 

Synergy Pharmaceuticals Announces Successful End-of-Phase 2 Meeting with FDA for Plecanatide in Irritable Bowel Syndrome with Constipation

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Pivotal Phase 3 IBS-C Program to be Initiated in the Fourth Quarter of 2014

NEW YORK– Synergy Pharmaceuticals Inc. (NASDAQ:SGYP) today announced that it has successfully completed an End-of-Phase 2 meeting with the U.S. Food and Drug Administration (FDA) on its lead drug plecanatide for the treatment of irritable bowel syndrome with constipation (IBS-C). Agreement was reached with the FDA for the plecanatide pivotal phase 3 IBS-C clinical development program that is scheduled to begin in the fourth quarter of this year.

“We are very pleased with the outcome of our meeting with the FDA and have a clear path forward to start the IBS-C registration program with plecanatide this year,” said Dr. Gary S. Jacob, Chairman and CEO of Synergy. “The pivotal phase 3 IBS-C trials will include both 3.0 mg and 6.0 mg plecanatide, which are consistent with the doses currently being evaluated in our phase 3 chronic idiopathic constipation (CIC) program. Plecanatide has demonstrated a clinical dose-response for efficacy with an excellent tolerability profile that is observed across trials. This is an important advantage as we look to bring two doses to market in both indications and provide physicians with options for addressing individual patient needs.”

Synergy’s pivotal phase 3 IBS-C clinical development program will consist of two registration trials, each including 1,050 patients who will receive either placebo, 3.0 mg or 6.0 mg plecanatide. IBS-C patients successfully completing either of the 12-week placebo-controlled registration trials will be offered enrollment into a long-term safety trial in order to complement and support the ongoing long-term safety database for the CIC indication.

About Plecanatide

Plecanatide is Synergy’s lead uroguanylin analog in late-stage clinical development to treat patients with CIC and IBS-C. Uroguanylin is a natural gastrointestinal (GI) hormone produced by humans in the small intestine and plays a key role in regulating the normal functioning of the digestive tract through its activity on the guanylate cyclase-C (GC-C) receptor. The GC-C receptor is known to be a primary source for stimulating a variety of beneficial physiological responses. Orally administered plecanatide mimics uroguanylin’s functions by binding to and activating the GC-C receptor to stimulate fluid and ion transit required for normal bowel function. Synergy has successfully completed a phase 2b trial of plecanatide in 951 patients with CIC and is currently enrolling patients in two pivotal phase 3 CIC trials. The company also recently announced positive top-line data results from a phase 2b dose-ranging study with plecanatide in patients with IBS-C.

About Synergy Pharmaceuticals

Synergy Pharmaceuticals (NASDAQ:SGYP) is a biopharmaceutical company focused on the development of novel therapies based on the natural human hormone, uroguanylin, to treat GI diseases and disorders. Synergy has created two unique analogs of uroguanylin – plecanatide and SP-333 – designed to mimic the natural hormone’s activity on the GC-C receptor and target a variety of GI conditions. SP-333 is currently in phase 2 development for opioid-induced constipation and is also being explored for ulcerative colitis. For more information, please visit www.synergypharma.com.

 

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False-Positive Mammogram Results May Be Linked to Higher Risk Later in Life

While screening mammograms aren’t perfect, they are the best way we have right now to detect breast cancer early, when it’s most treatable.

When a screening mammogram shows an abnormal area that looks like a cancer but turns out to be normal, it’s called a false positive. Ultimately the news is good: no breast cancer. But the suspicious area usually requires follow-up with more than one doctor, extra tests, and extra procedures, including a possible biopsy.

A large study suggests that women with false-positive mammogram results have a slightly higher risk of developing invasive breast cancer within the next 10 years.

The research was published online on Dec. 2, 2015 by the journal Cancer Epidemiology, Biomarkers & Prevention. Read the abstract of “Increased Risk of Developing Breast Cancer after a False-Positive Screening Mammogram.”

To do the study, the researchers looked at information from nearly 1.3 million women ages 40 to 70 with no family history of breast cancer who had screening mammograms from 1994 to 2009. The information came from the Breast Cancer Surveillance Consortium database, which is maintained by the National Cancer Institute.

The researchers found that the 1,297,906 women had a total of 2,207,942 screening mammograms. There were:

  • 159,448 false-positive results with a recommendation for more imaging
  • 22,892 false-positive results with a recommendation for biopsy
  • 2,025,602 negative mammograms

Women ages 40 to 49 made up the largest percentage of false-positive mammogram results with a recommendation for more imaging (33.1%). Women with dense breasts also were more likely to have false-positive results.

The researchers then compared the rates of invasive breast cancer between women who had false-positive mammogram results and women who had negative mammogram results:

  • there were 3.91 invasive breast cancers per 1,000 person-years of follow-up among women with negative mammogram results
  • there were 5.51 invasive breast cancers per 1,000 person-years of follow-up among women with false-positive mammogram results with a recommendation for more imaging
  • there were 7.01 invasive breast cancers per 1,000 person-years of follow-up among women with false-positive mammogram results with a recommendation for biopsy

The researchers said the 10-year risk of invasive breast cancer was:

  • 39% higher in women with false-positive results with a recommendation for more imaging
  • 76% higher in women with false-positive results with a recommendation for biopsy

compared to women with negative results.

It’s important to know that the increases above are increases in relative risk — the risk of a woman with a false-positive result relative to the risk of a woman with a negative result.

In terms of absolute risk, the increase is small:

  • women with false-positive results have about a 2% risk of developing invasive disease in the 10 years after the false-positive result
  • women with negative results have about a 1% risk of developing invasive disease in the 10 years after the negative result

The researchers didn’t offer an explanation about why false-positive mammogram results appear to be linked to a slightly higher risk of invasive disease. Many experts think that the subtle changes suggested on the mammogram may be an early clue to cancer before actual cancer exists.

It’s also important to know that this association has been suggested in other studies. But the large number of women in the study and the length of follow-up add more evidence that the link between false-positive results and a somewhat higher risk of invasive disease actually exists.

“The power of this study to show the association is very strong, particularly when you combine it with the results of the other studies that have been done,” said Richard Wender, M.D., chief of cancer control at the American Cancer Society, in an interview. “I think we can now say with confidence that women who have had a previous false-positive mammogram are at somewhat higher risk for breast cancer.”

The researchers who did this study want to incorporate false-positive mammogram results into models that predict breast cancer risk.

“Now that we have this information, our hope is that we can add it into existing risk-prediction models to improve their ability to discriminate between women who will go on to develop breast cancer and those who won’t,” said Louise Henderson, Ph.D., of the University of North Carolina Lineberger Comprehensive Cancer Center, who was the lead author of the study. “We should accept that a false-positive mammogram is a risk factor for predicting future risk of breast cancer.

“In clinical terms, that means women who have a false-positive mammogram need to be particularly vigilant about keeping up with regular mammographic screening,” she continued. “The clinicians caring for these women should have a way to track women who have had a false-positive and make sure that every effort is made to keep up to date with mammography.”

It’s important to know that a false-positive mammogram result doesn’t mean you will be diagnosed with breast cancer.

“Having any history of breast biopsies is associated with a higher risk,” said Breastcancer.org President and Founder Marisa Weiss, M.D. “Breast tissue that is dense or has proliferative changes tends to lead to questions on the breast imaging. Sometimes it leads to biopsies. In contrast, breast tissue that is boring, without any extra activity, rarely leads to any kind of biopsy. That kind of inactive breast tissue is less likely to develop breast cancer.”

“This study doesn’t suggest that having a false-positive leads to breast cancer,” said Brian Wojciechowski, M.D., Breastcancer.org’s medical adviser. “Rather, it reflects an association between breast cancer risk and abnormal breast imaging. Women should not worry that getting mammograms will increase their risk of breast cancer in the future.”

There’s only one of you and you deserve the best care possible. Don’t let any obstacles get in the way of your regular screening mammograms, especially if you’ve had a false-positive result.

  • If you’re worried about cost, talk to your doctor, a local hospital social worker, or staff members at a mammogram center. Ask about free programs in your area.
  • If you’re having problems scheduling a mammogram, call the National Cancer Institute (800-4-CANCER) or the American College of Radiology (800-227-5463) to find certified mammogram providers near you.
  • If you find mammograms painful, ask the mammography center staff members how the experience can be as easy and as comfortable as possible for you.
  • If you’re concerned about unknown results or being called back for more testing, talk to your doctor about what happens when mammogram results are unclear, as well as what to expect if you’re called back for more testing.

For more information on mammograms and other tests to detect and diagnose breast cancer, visit the Breastcancer.org Screening and Testing section.


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PD1 Inhibitor atezolizumab may show promise in bladder cancer in patients with high PDL1 expression

Reporter: Stephen J Williams

Updated 4/15/2016

Promising Immunotherapy Agents on Horizon in Bladder Cancer

Reported from OncLive

Virginia Powers, PhD

Published Online: Monday, November 16, 2015 at http://www.onclive.com/web-exclusives/promising-immunotherapy-agents-on-horizon-in-bladder-cancer

 

thompson

Thomas Powles, MD

The dramatic and often practice-changing findings demonstrated by trials of immunotherapies in melanoma and lung cancer may soon be reflected in the treatment of bladder cancer, according to a summary of ongoing studies1 presented at the 7th European Multidisciplinary Meeting on Urological Cancers (EMUC).

“Immune therapy is a promising new treatment in transitional cell carcinoma (TCC) of the bladder,” said Thomas Powles, MD, medical oncologist, director of St Bartholomew’s Cancer Centre, London. “Until recently, bladder cancer research has been somehow left behind.”

Powles underscored that immune checkpoint inhibitors are active in urothelial bladder cancer (UBC) and provided an overview of the emergence of immune therapy in bladder cancer that focused on agents targeting the immune checkpoint axis, especially the programed death receptor (PD1) and its ligand (PD-L1).

“Each drug has a unique companion diagnostic but the strongest data so far are seen with blocking PD-L1 and atezolizumab,” he said.

The confirmed overall response rate (ORR) by RECIST to atezolizumab are associated with PD-L1 expression levels in the tumor. In a phase I trial of second line atezolizumab (MPDL3280A) in TCC, a response was demonstrated in patients that had previously showed only a 10% response rate to chemotherapy. The ORRs were 43% for patients with tumors expressing high levels of PD-L1 (IHC 2/3) compared to 11% in patients with tumors having low expression (IHC 0 or 1).2

PD-L1 expression on the immune cells (IC) infiltrating the tumor has also been shown to be associated with response. The PD-L1 expression on ICs was evaluated as low, medium, and high in approximately one-third each of 311 patients with locally-advanced or metastatic urothelial carcinoma (mUC) participating in the phase II IMvigor 210 trial, which corresponded to an ORR with atezolizumab of 9%, 10%, and 27% in the respective expression groups.

Overall survival (OS) at a median follow-up of 7 months (range, 0-11) also correlated with expression levels and was 6.7 months in low (IC0/1), not reached in high (IC2/3) expressing patients, and 7.9 months in overall population. However, no difference was seen in progression-free survival (PFS) according to expression levels; median PFS was 2.1 months in the overall population and in patients having both low (IC0/1) and high (IV2/3) expression levels, respectively. These data were emphasized as early response data that are expected to mature in further analyses.3

Powles commented that his team is beginning a phase III randomized trial of atezolizumab in 767 patients with locally-advanced UBC who were also chemotherapy-resistant following 1 to 2 prior lines of a platinum-based regimen. Patients have been stratified by chemotherapy regimen, PD-L1 expression, IHC status, risk factors, and the presence of liver metastasis. The primary endpoint is OS and secondary endpoints include ORR, PFS, and duration of response (DoR), safety, and tolerability. Other objectives include disease control rate and potential biomarkers.

“PD-L1 expression appears important but we need to find other biomarkers,” he remarked.

Powles moved on to discuss the KEYNOTE-012 phase Ib trial of pembrolizumab, an anti-PD1 antibody that blocks interaction with both PD-L1 and PD-L2. In KEYNOTE, pembrolizumab demonstrated anti-tumor activity in patients with recurrent or metastatic PD-L1–positive UBC in 64% of patients experiencing a decrease in target lesions from baseline.4

Combination and adjuvant studies are ongoing, according to Powles. A trial of atezolizumab as adjuvant therapy versus placebo is underway in patients with TCC whose tumors express PD-L1. The trial has a primary endpoint of disease-free survival (DFS).

“Next-generation combination therapy with nivolumab plus ipilimumab is a common sense approach that was tested in advanced melanoma and is now being evaluated in the Danube trial,” Powles said.

Nivolumab, a PD-1 blocking antibody, and ipilimumab, which blocks CTLA-4, will be evaluated in Danube, a randomized phase III study that will enroll 800 patients with untreated metastatic TCC. The endpoints are PFS and OS. Patients are required to have available tissue for PD-L1 testing and no contraindications for immune therapy.

The rationale for the combination was demonstrated in melanoma, where confirmed objective responses were seen in 61% of patients receiving nivolumab plus ipilimumab versus 11% in patients receiving ipilimumab and placebo (P <0.001). Complete responses were reported in 16 patients (22%) with combination compared to no patients receiving ipilimumab monotherapy.5

“It looks like checkpoint inhibition works particularly well in node positive patients; in the future we can see treatment with first-line immunotherapeutic agents,” said Powles.

“We hope that immune therapy will identify a subset of patients who get long-term benefits from immune therapy,” Powles said. “The future looks bright for immunotherapy in bladder cancer.”

References

  1. Powles T. Update on systemic treatments in bladder cancer. Presented at: 7th European Multidisciplinary Meeting on Urological Cancers (EMUC), Barcelona, Spain, November 12–15, 2015.
  2. Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014;515(7528):558-562.
  3. Rosenberg J, Petrylak D, Abidoye O, et al. Atezolizumab in patients (pts) with locally-advanced or metastatic urothelial carcinoma (mUC): Results from a pivotal multicenter phase II study (IMvigor 210). Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 21LBA.
  4. Plimack ER, Bellmunt J, Gupta S, et al. Pembrolizumab (MK-3475) for advanced urothelial cancer: Updated results and biomarker analysis from KEYNOTE-012. J Clin Oncol 33, 2015 (suppl; abstr 4502).
  5. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015; 373:23-34.

– See more at: http://www.onclive.com/web-exclusives/promising-immunotherapy-agents-on-horizon-in-bladder-cancer#sthash.c63jReGo.dpuf

Speedy review for Merck’s Keytruda in head and neck cancer

DAILY NEWS | APRIL 14, 2016

SELINA MCKEE

Speedy review for Merck's Keytruda in head and neck cancer

US regulators have agreed to undertake a speedy review of Merck & Co’s application to market immunotherapy Keytruda for the treatment of certain patients with head and neck cancer, it third potential indication in the country.

 

The company is targeting the drug towards patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.

 

“We are encouraged by the data emerging from our program in this type of cancer, and welcome today’s news as this is an important step toward making Keytruda (pembrolizumab) available to these patients,” said Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories.

 

The US Food and Drug Administration has set an action date for Keytruda – an anti-PD-1 therapy dosed as a single agent intravenously every three weeks – of August 9.

 

Keytruda is a humanised monoclonal antibody that boosts the ability of the body’s immune system to help detect and fight tumour cells. The drug has already racked up approvals in melanoma and lung cancer in the US.

Read more at: http://www.pharmatimes.com/Article/16-04-14/Speedy_review_for_Merck_s_Keytruda_in_head_and_neck_cancer.aspx#ixzz45uMyaCdc
Follow us: @PharmaTimes on Twitter

 

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Lab Grown Brains and more from Twittersphere on 3D Bio-Printing News

Curator: Stephen J. Williams, Ph.D

How Tiny Lab-Grown Human Brains Are Giving Big Insights Into Autism and more from the Twittershpere

 

https://twitter.com/singularityhub/status/664508353771610112

(more…)

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FDA Guidance On Source Animal, Product, Preclinical and Clinical Issues Concerning the Use of Xenotranspantation Products in Humans – Implications for 3D BioPrinting of Regenerative Tissue

Reporter: Stephen J. Williams, Ph.D.

 

The FDA has submitted Final Guidance on use xeno-transplanted animal tissue, products, and cells into human and their use in medical procedures. Although the draft guidance was to expand on previous guidelines to prevent the introduction, transmission, and spread of communicable diseases, this updated draft may have implications for use of such tissue in the emerging medical 3D printing field.

This document is to provide guidance on the production, testing and evaluation of products intended for use in xenotransplantation. The guidance includes scientific questions that should be addressed by sponsors during protocol development and during the preparation of submissions to the Food and Drug Administration (FDA), e.g., Investigational New Drug Application (IND) and Biologics License Application (BLA). This guidance document finalizes the draft guidance of the same title dated February 2001.

For the purpose of this document, xenotransplantation refers to any procedure that involves the transplantation, implantation, or infusion into a human recipient of either (a) live cells, tissues, or organs from a nonhuman animal source, or (b) human body fluids, cells, tissues or organs that have had ex vivo contact with live nonhuman animal cells, tissues or organs. For the purpose of this document, xenotransplantation products include live cells, tissues or organs used in xenotransplantation. (See Definitions in section I.C.)

This document presents issues that should be considered in addressing the safety of viable materials obtained from animal sources and intended for clinical use in humans. The potential threat to both human and animal welfare from zoonotic or other infectious agents warrants careful characterization of animal sources of cells, tissues, and organs. This document addresses issues such as the characterization of source animals, source animal husbandry practices, characterization of xenotransplantation products, considerations for the xenotransplantation product manufacturing facility, appropriate preclinical models for xenotransplantation protocols, and monitoring of recipients of xenotransplantation products. This document recommends specific practices intended to prevent the introduction and spread of infectious agents of animal origin into the human population. FDA expects that new methods proposed by sponsors to address specific issues will be scientifically rigorous and that sufficient data will be presented to justify their use.

Examples of procedures involving xenotransplantation products include:

  • transplantation of xenogeneic hearts, kidneys, or pancreatic tissue to treat organ failure,
  • implantation of neural cells to ameliorate neurological degenerative diseases,
  • administration of human cells previously cultured ex vivo with live nonhuman animal antigen-presenting or feeder cells, and
  • extracorporeal perfusion of a patient’s blood or blood component perfused through an intact animal organ or isolated cells contained in a device to treat liver failure.

The guidance addresses issues such as:

  1. Clinical Protocol Review
  2. Xenotransplantation Site
  3. Criteria for Patient Selection
  4. Risk/Benefit Assessment
  5. Screening for Infectious Agents
  6. Patient Follow-up
  7. Archiving of Patient Plasma and Tissue Specimens
  8. Health Records and Data Management
  9. Informed Consent
  10. Responsibility of the Sponsor in Informing the Patient of New Scientific Information

A full copy of the PDF can be found below for reference:

fdaguidanceanimalsourcesxenotransplatntation

An example of the need for this guidance in conjunction with 3D printing technology can be understood from the below article (source http://www.geneticliteracyproject.org/2015/09/03/pig-us-xenotransplantation-new-age-chimeric-organs/)

Pig in us: Xenotransplantation and new age of chimeric organs

David Warmflash | September 3, 2015 | Genetic Literacy Project

Imagine stripping out the failing components of an old car — the engine, transmission, exhaust system and all of those parts — leaving just the old body and other structural elements. Replace those old mechanical parts with a brand new electric, hydrogen powered, biofuel, nuclear or whatever kind of engine you want and now you have a brand new car. It has an old frame, but that’s okay. The frame wasn’t causing the problem, and it can live on for years, undamaged.

When challenged to design internal organs, tissue engineers are taking a similar approach, particularly with the most complex organs, like the heart, liver and kidneys. These organs have three dimensional structures that are elaborate, not just at the gross anatomic level, but in microscopic anatomy too. Some day, their complex connective tissue scaffolding, the stroma, might be synthesized from the needed collagen proteins with advanced 3-D printing. But biomedical engineering is not there yet, so right now the best candidate for organ scaffolding comes from one of humanity’s favorite farm animals: the pig.

Chimera alarmists connecting with anti-biotechnology movements might cringe at the thought of building new human organs starting with pig tissue, but if you’re using only the organ scaffolding and building a working organ from there, pig organs may actually be more desirable than those donated by humans.

How big is the anti-chimerite movement?

Unlike anti-GMO and anti-vaccination activists, there really aren’t too many anti-chemerites around. Nevertheless, there is a presence on the web of people who express concern about mixing of humans and non-human animals. Presently, much of their concern is focussed on the growing of human organs inside non-human animals, pigs included. One anti-chemerite has written that it could be a problem for the following reason:

Once a human organ is grown inside a pig, that pig is no longer fully a pig. And without a doubt, that organ will no longer be a fully human organ after it is grown inside the pig. Those receiving those organs will be allowing human-animal hybrid organs to be implanted into them. Most people would be absolutely shocked to learn some of the things that are currently being done in the name of science.

The blog goes on to express alarm about the use of human genes in rice and from there morphs into an off the shelf garden variety anti-GMO tirade, though with an an anti-chemeric current running through it. The concern about making pigs a little bit human and humans a little bit pig becomes a concern about making rice a little bit human. But the concern about fusing tissues and genes of humans and other species does not fit with the trend in modern medicine.

Utilization of pig tissue enters a new age 

pigsinus

A porcine human ear for xenotransplantation. source: The Scientist

For decades, pig, bovine and other non-human tissues have been used in medicine. People are walking around with pig and cow heart valves. Diabetics used to get a lot of insulin from pigs and cows, although today, thanks to genetic engineering, they’re getting human insulin produced by microorganisms modified genetically to make human insulin, which is safer and more effective.

When it comes to building new organs from old ones, however, pig organs could actually be superior for a couple of reasons. For one thing, there’s no availability problem with pigs. Their hearts and other organs also have all of the crucial components of the extracellular matrix that makes up an organ’s scaffolding. But unlike human organs, the pig organs don’t tend to carry or transfer human diseases. That is a major advantage that makes them ideal starting material. Plus there is another advantage: typically, the hearts of human cadavers are damaged, either because heart disease is what killed the human owner or because resuscitation efforts aimed at restarting the heart of a dying person using electrical jolts and powerful drugs.

Rebuilding an old organ into a new one

How then does the process work? Whether starting with a donated human or pig organ, there are several possible methods. But what they all have in common is that only the scaffolding of the original organ is retained. Just like the engine and transmission of the old car, the working tissue is removed, usually using detergents. One promising technique that has been applied to engineer new hearts is being tested by researchers at the University of Pittsburgh. Detergents pumped into the aorta attached to a donated heart (donated by a human cadaver, or pig or cow). The pressure keeps the aortic valve closed, so the detergents to into the coronary arteries and through the myocardial (heart muscle) and endocardial (lining over the muscle inside the heart chambers) tissue, which thus gets dissolved over the course of days. What’s left is just the stroma tissue, forming a scaffold. But that scaffold has signaling factors that enable embryonic stem cells, or specially programed adult pleuripotent cells to become all of the needed cells for a new heart.

Eventually, 3-D printing technology may reach the point when no donated scaffolding is needed, but that’s not the case quite yet, plus with a pig scaffolding all of the needed signaling factors are there and they work just as well as those in a human heart scaffold. All of this can lead to a scenario, possibly very soon, in which organs are made using off-the-self scaffolding from pig organs, ready to produce a custom-made heart using stem or other cells donated by new organ’s recipient.

David Warmflash is an astrobiologist, physician, and science writer. Follow @CosmicEvolution to read what he is saying on Twitter.

And a Great Article in The Scientist by Dr. Ed Yong Entitled

Replacement Parts

To cope with a growing shortage of hearts, livers, and lungs suitable for transplant, some scientists are genetically engineering pigs, while others are growing organs in the lab.

By Ed Yong | August 1, 2012

Source: http://www.the-scientist.com/?articles.view/articleNo/32409/title/Replacement-Parts/

.. where Joseph Vacanti and David Cooper figured that using

“engineered pigs without the a-1,3-galactosyltransferase gene that produces the a-gal residues. In addition, the pigs carry human cell-membrane proteins such as CD55 and CD46 that prevent the host’s complement system from assembling and attacking the foreign cells”

thereby limiting rejection of the xenotransplated tissue.

In addition to issues related to animal virus transmission the issue of optimal scaffolds for organs as well as the advantages which 3D Printing would have in mass production of organs is discussed:

To Vacanti, artificial scaffolds are the future of organ engineering, and the only way in which organs for transplantation could be mass-produced. “You should be able to make them on demand, with low-cost materials and manufacturing technologies,” he says. That is relatively simple for organs like tracheas or bladders, which are just hollow tubes or sacs. Even though it is far more difficult for the lung or liver, which have complicated structures, Vacanti thinks it will be possible to simulate their architecture with computer models, and fabricate them with modern printing technology. (See “3-D Printing,” The Scientist, July 2012.) “They obey very ordered rules, so you can reduce it down to a series of algorithms, which can help you design them,” he says. But Taylor says that even if the architecture is correct, the scaffold would still need to contain the right surface molecules to guide the growth of any added cells. “It seems a bit of an overkill when nature has already done the work for us,” she says.

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