StemCell Therapy

An image of HIV from a scanning electron microscope. A vaccine project is in very early stages, but it's sparking interest among scientists in the field.

Ever since the AIDS epidemic erupted nearly 40 years ago, researchers have tried to make a vaccine.

The efforts typically end up like this: "Failure Of Latest HIV Vaccine Test: A 'Huge Disappointment.' "

Now researchers have come up with a new blueprint.

The method behind their potential vaccine mimics a rare process detected in the immune systems of some people with HIV a process the reduces the amount of virus in the body.

The team from Duke and Harvard behind the work, which appears this month in the journal Science, says there is still a long road ahead before an actual vaccine is ready for large-scale field trials. But scientists in the field are more optimistic than they've been for some time.

"For the first 20 years after the virus was discovered, the field tried to make a vaccine using the techniques that all the successful measles, mumps, rubella, polio vaccines had been made with in the past. And none of those worked," says Barton Haynes, director of the Duke Human Vaccine Institute and a lead author of the new research. But with a virus that's constantly mutating to evade the immune system, the antibodies generated weren't strong enough to fight it off.

But in about 20% of people who get infected with HIV, their immune systems will make special proteins called "broadly neutralizing antibodies." These antibodies live up to their name by wiping out many different strains of HIV by attacking the parts of the virus that stay constant, even as it evolves.

These proteins tend to develop several years after infection and can stop the virus from replicating for a while although they don't cure people of HIV because there's always a reservoir of the virus hiding out in cells where antibodies can't reach them.

But earlier tests in animals showed a powerful way forward: When they were infused with these antibodies before exposure to HIV, infections were prevented.

But there was a problem: The protection was short-lived.

In the new research, Haynes and his colleagues use computer modeling and lab testing on mice and monkeys to figure out how to train an immune system that's not been compromised by HIV to create these special antibodies and then continue to make new, stronger generations.

"We show a new way to design the HIV vaccine to guide the broadly neutralizing antibodies to go down paths they rarely go down on their own," Haynes says. The vaccine would also train the immune system to make these antibodies in months instead of the natural timetable of years after human exposure to the virus.

The approach looks promising to Rowena Johnston, research director at the nonprofit Foundation for AIDS Research, or amfAR, who was not involved with the study. "Nature is the best engineer when it comes to working out what our immune system should do," she says.

A vaccine based on these antibodies also has the potential to be far more effective than others in development. There currently are three HIV vaccine candidates in the final stages of human testing, and they'll be considered successful if they protect just half the exposed population from getting HIV. The benefit of this new method is that because it's introducing more powerful antibodies than the other vaccine candidates, it could lead to a vaccine that is 80-90% effective, says Dr. John Mascola, director of the Vaccine Research Center at the National Institutes of Health (NIH), who was not involved with the study.

Haynes' team is a third of the way through developing several of these antibodies, and they'll need more types to make an effective vaccine, something they say they're confident they'll be able to do.

Mascola estimates that it will take at least another five years for an HIV vaccine based on this research to get to large-scale clinical trials.

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HIV Vaccine Researchers Unveil New Strategy In Fight Against HIV : Goats and Soda - NPR

The UAB freshman immunology honors seminar recently held a Q&A with Pulitzer Prize-winning newspaper reporter Matt Richtel.

The human immune system makes my head explode, Pulitzer Prize-winning journalist Matt Richtel recently told a University of Alabama at Birmingham freshman seminar on immunology. This is by far the hardest subject I have ever had to explore.

Richtel, a longtime New York Times reporter, was explaining why he wrote his general interest book An Elegant Defense The Extraordinary New Science of the Immune System, which the class was reading.

Richtels curiosity began when his boyhood buddy Jason Greenstein, the best kind of jock, got cancer in his 40s.

He had 15 pounds of cancer, went into hospice and was supposed to die, Richtel said through a video link with the UAB Honors College freshman seminar. However, when Greenstein who had nine toes in the grave got experimental immunotherapy, the cancer disappeared, though Greenstein later died. I didnt understand, Richtel said. What is this thing called the immune system, that they can tinker with to keep us alive?

Indeed, what is this thing, which is so complex and important in human health, development and disease? The UAB seminar freshmen are just beginning to scratch its surface.

In many ways, immunology is as challenging a major as neuroscience, another undergraduate major found in the UAB College of Arts and Sciences and at many other colleges.

Both the nervous system and the immune system are composed of a widespread network of organs, tissues, cells and soluble mediators that work together. Both systems interface with every organ in the body, as well as each other. Each plays critical roles in health and disease, and both require years of study for a student to grasp how the system works, and to tread a landslide of nitty-gritty mechanistic interactions that regulate normal function, or that misfire to cause disease, dysfunction and, sometimes, death.

Yet the two majors have a difference. Neuroscience is far more obvious. Each of us knows we have a brain. We daily experience five senses that report the world around us and convey pleasure or pain. Many of us have relatives or older friends who suffer the visible signs of neurodegenerative disease.

Immunology lacks this focus. Where or how does the immune system operate? What are its components? For most of us, the immune system is a vast, foggy landscape where many important things happen beneath our notice.

These differences explain, perhaps, why the number of neuroscience undergraduate majors has boomed in the past three decades, while in-depth immunology undergraduate majors still remain few. One of the few is UABs major, begun in 2017.

Three UAB faculty assert the need to revolutionize undergraduate immunology education in a Frontiers in Immunology paper.

The UAB immunology joint-health program in the UAB Department of Biology and Department of Microbiology is a four-year curriculum. After the freshman UAB honors seminar, full-semester courses include current topics in immunology, the innate immune system, the adaptive immune system, the microbial pathogen-immune system interaction, and immunologically mediated diseases.

The education is wide-ranging, and students also work in laboratories, readying themselves for careers in the health professions or research.

Immunology, by nature, is interdisciplinary, said Lou Justement, Ph.D., the teacher, along with Heather Bruns, Ph.D., of the honors seminar. Both are microbiology faculty in the UAB School of Medicine. It requires a knowledge of cellular and molecular biology, genetics, biochemistry, physiology, and anatomy. Freshmen are introduced to medically related conceptual frameworks that continue through the four-year curriculum how immunology relates to vaccines, emerging infectious diseases, autoimmunity, allergy, transplantation, cancer and immunotherapy. Students learn how the immune system is relevant to health and disease.

Richtel took a different approach. Rather than write an immunology textbook, he put faces on the role of immunology in health and disease. Parts of An Elegant Defense tell the stories of Jason, Bob, Linda and Merredith, and the burdens they faced Hodgkins lymphoma, HIV infection, rheumatoid arthritis and lupus. Richtel also relates surprising twists and turns for basic researchers who studied the immune system. Its a story, he writes at one point, that begins with a bird, a dog and a starfish.

During the video Q&A with students, Richtel wore a UAB T-shirt. Most of the UAB students asked how he reported and wrote the book. One of the hardest things to do when writing is to find your framework that will pay off the reader as you promised, he said.

And Richtel asked questions right back, offering guide stones of advice for the students:

UAB freshman Chandni Modi was one of the enthusiastic participants in the Q&A with Richtel. Afterward, the Indian Springs School graduate said, Honestly, at the beginning of my high school senior year, UAB wasnt one of my top choices. However, after I started comparing my options, UAB was the only school that offered immunology as a major, and UAB offers so many ways to get involved in research.

Also, she said, I appreciated how diverse the university students and faculty are.

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The smart-dumb question, a key to writing about and understanding immunology - The Mix

The human immune system is highly complex and multi-faceted. Seemingly an infinite number of things can affect our internal landscape and alter how our immune system defenses respond to and fight foreign invaders to keep us healthy. The misconception a lot of people have is thinking that we want a super active immune system that is like Rambo, an ultimate killing machine! Really what we want is a balanced immune system, that neither swings into hyperactivity nor falls into decreased function. If our immune system functions too high, we end up with autoimmune disorders this is when the immune system attacks our bodys cells, not just foreign invaders, if it is not functioning as it should, when exposed to germs we get sick and have to fight off an illness.

Did you know that just the time of year can affect our immune system function? Just the fact that the daylight does not last as long can cause our immune system to be less responsive. Shorter days and colder weather cause people to stay inside more, reducing the amount of natural vitamin D they make, which is a key immune system booster. An alternative for the individual not wanting to go outside is supplementing Vitamin D into their diet.

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Seasonally Decreased Immune Function Around the Holidays - Matthews Beacon

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By Sarah C.P. Williams

Newswise UCLA scientists have discovered one reason why autoimmune diseases are more prevalent in women than in men. While males inherit their mothers X chromosome and fathers Y chromosome, females inherit X chromosomes from both parents. New research, which shows differences in how each of those X chromosomes is regulated, suggests that the X chromosome that females get from their father may help to explain their more active immune system.

Its been known for many years that women are more susceptible to autoimmune diseases than men are, said lead study author Dr. Rhonda Voskuhl, a UCLA professor of neurology and director of the UCLA Multiple Sclerosis Program who also holds the Jack H. Skirball Chair in Multiple Sclerosis Research. Figuring out why can help us develop new drugs to treat these autoimmune diseases.

Autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis, are conditions that affect the bodys ability to fight viruses, bacteria and infections. The problem causes a persons immune cells to attack the body instead.

Women generally have stronger immune responses than men, with more robust responses to some vaccinations and infections. However, this heightened immune system also makes women three times more likely than men to develop multiple sclerosis, nine times more likely to develop lupus ,and more prone to a host of other autoimmune diseases, Voskuhl said. The effect of sex hormones testosterone and estrogen in these differences has been well-studied, but the role of sex chromosomes has been less clear.

In thenew work, published in Proceedings of the National Academy of Sciences, Voskuhl and her colleagues focused on differences between the X chromosomes inherited from each parent. They first analyzed expression levels of genes in mice with the male (XY) and female (XX) chromosome set. They identified a handful of immune system-related genes on the X chromosome that are expressed less producing fewer corresponding molecules in the immune cells of female mice.

To further study these differences, the Voskuhl team next compared mice that had just one X chromosome either a maternal or paternal X chromosome. They determined levels of methylation the addition of methyl chemical groups to DNA in the X chromosomes. Methylation is known to turn down, or block, the expression of genes. And while the methyl groups arent part of the DNA sequence itself, patterns of methylation can be passed from parent to child. The researchers discovered that there was more methylation on paternal than on maternal X chromosomes. Finally, they confirmed that several genes on the X chromosome were expressed less when the X chromosome was of paternal as compared to maternal origin.

What were talking about here is not mutations that affect gene sequences, but instead signals that affect how the same sequence of genes are differentially expressed in females versus males. These differences would be missed in traditional genetic studies, Voskuhl said.

The findings suggest that the X chromosomes packaged into sperm and passed from father to daughter may have higher levels of methylation than the X chromosomes passed along in eggs from a mother to her offspring. This methylation dampens the expression of some immune system genes in females, making their immune activity different from males.

If you can find regulators of methylation that target these differences, you might be able to reduce the immune responses of females to treat autoimmune diseases, Voskuhl said. Going forward, when one considers sex as a biologic variable in diseases, it can lead to new treatment strategies.

More work is needed to determine whether the same is seen in humans as mice and whether the methylation differences lead to measurable differences in autoimmune disease risk. Voskuhl said the new research is an important step toward better understanding sex differences in disease, a goal that the National Institutes of Health underscored the importance of in 2016 when it mandated that researchers consider sex as a biological variable in their grant applications.

The first authors of the study are graduate student Lisa Golden and associate researcher Yuichiro Itoh, both of UCLA.

Study funders include the National Institutes of Health, the Conrad N. Hilton Foundation, the Tom Sherak MS Hope Foundation and the Rhoda Goetz Foundation for Multiple Sclerosis.

SEE ORIGINAL STUDY

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Father's X chromosome may yield clues to higher rates of autoimmune disease in women - Newswise

The idea of a cell therapy for Parkinsons disease starts out simple: Symptoms of the progressive disease are largely driven by the deaths of dopamine-producing neurons found deep within the brain. With lower levels of the neurotransmitter come the characteristic tremors, rigidity and slow movements.

By replacing those lost nerve cells with new dopamine producers, researchers hope to renew the brains connection to the bodys muscles and improve a persons overall motor function.

But in the brain, everything becomes more complicated. On top of the risk of immune system rejection that comes with any kind of living tissue transplant, its important to make sure the implanted cells function correctly and do not pick up any dangerous genetic mutations as they grow.

How ICON, Lotus, and Bioforum are Improving Study Efficiency with a Modern EDC

CROs are often at the forefront of adopting new technologies to make clinical trials more efficient. Hear how ICON, Lotus Clinical Research, and Bioforum are speeding database builds and automating reporting tasks for data management.

Now, a new company, Aspen Neuroscience, aims to tackle both obstacles at once.

First, the startup hopes to avoid any harmful immune reactions by using a patients own cells as a starting point. Then, Aspen plans to implement a rigorous quality control program employing whole genome sequencing and artificial intelligence to make sure the cells stay in line as theyre processed and readied for the procedure.

And to do it, the San Diego-based company is starting out with $6.5 million in seed money plus an impressive roster of names.

They are led by neurology researcher Howard Federoff, previously vice chancellor for health affairs and CEO of the University of California, Irvine health system as well as the executive dean of medicine at Georgetown University. Hes joined by Aspen co-founder and stem cell scientist Jeanne Loring, founding director and professor emeritus of the Center for Regenerative Medicine at the Scripps Research Institute.

Meanwhile, the seed round was led by Domain Associates and Axon Ventures with additional backing from Alexandria Venture Investments, Arch Venture Partners, OrbiMed and Section 32.

Aspen looks to combine its expertise in stem cell biology, genomics and neurology to offer the first autologous cell therapy for Parkinsons diseasewhile others in the space have pursued allogeneic routes, or therapies derived from donors other than the patient.

The process starts with a culture of the patients skin cells, which are then genetically induced to become pluripotent stem cellsor cells capable of differentiating into any other cell type in the body. These are then chemically nudged further to transform into precursor versions of the dopamine-producing neurons, which are typically found in the midbrain and regions responsible for the movement of limbs.

We can say without any equivocation that we can produce the population of cells necessary to transplant, and in a short enough period of time to have a potential beneficial impact on the evolution of the disease, said Federoff, who has also served as chair of the NIHs Recombinant DNA Advisory Committee and helped lead the U.S. Parkinsons Disease Gene Therapy Study Group.

We envisage that this will set back the clock on patients who have Parkinsons, unlike any other therapy that we know of, he told FierceMedTech in an interview.

The number of cells needed would be much smaller compared to other cell therapies and cancer treatments. The healthy human brain contains only about 200,000 dopamine-producing nerve cells, split between its two hemispheres, while patients with Parkinsons disease have lost about 50% or more of those neurons.

Aspen aims to evaluate two doses: one that aims to replace about 60% to 65% of a persons normal cell complement and another larger treatment, Federoff said.

Those smaller doses, as well as starting with a patients donor cells, help make the treatment safer to produce by requiring fewer steps. Each cycle of cell division and multiplication to increase their numbers carries the risk of introducing genetic mutations.

As the cells are grown, they are consistently evaluated with data-driven techniques pioneered by Lorings laboratory. Using whole genome RNA sequencing, Aspen will match the cells up at every stage with a genetic barcode taken from each patient at the start. This will allow them to look for changes, duplications or deletions in the pluripotent stem cell genome.

If the cells harbor mutations that are cancer drivers, we don't want to put those into people, Loring said. The only way is to check the sequencing before we transplant them.

The cells used in the transplant procedure arent fully grown; as neuron progenitors, they mimic the development steps seen in the brain of a growing fetus after theyre placed in the body as they wire themselves up to other neural structures and begin to form new networks of their own.

We anticipate that they will manufacture and release dopamine in a manner that is consistent with synaptic neurotransmission and the process of communicating from cell-to-cell, said Federoff. They will take up dopamine from synapses when it has done its business, bring it back into the cell, and prepare it for another synaptic release.

These are not just dopamine pumps, theyre real neurons, added Loring. They will genuinely replace the cells that have been lost in every way.

Aspen plans to pursue two courses of therapy, for the two major types of Parkinsons disease. Their lead candidate is for idiopathic, or sporadic Parkinsons, while their second is a CRISPR-edited version of the therapy designed to address one of the diseases most common genetic mutations, linked to about 5% of cases.

This would not only aim to restart dopamine production in this orphan indication, but also restore the damaged enzyme GBA, which is seen as an underlying cause. Federoff and Loring expect their sequencing-based quality check system will also help catch any off-target edits linked to the use of CRISPR-Cas9.

The company has yet to secure permission from the FDA to officially launch clinical trials, but the agency has signed off on Aspens plans to prepare a trial-ready cohort of Parkinsons disease patients in the meantime. This would include the initial stages of recruitment and testing, including the selection of patients capable of having their skin cells made into pluripotent stem cells.

After it receives its go-ahead from the FDA, Aspen plans to hit the ground running,enrolling at least 176 participants in a phase 1/2 study that includes a randomized stage to determine clinical benefits.

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By turning stem cells into brain cells, Aspen Neuroscience hopes to rewind the progress of Parkinson's disease - FierceBiotech

The new field of immunometabolism is the study of how metabolic pathways control immune cell differentiation and function

Rheos Medicines, a biopharmaceutical company harnessing insights in immunometabolism to create a new class of therapeutics for patients with severe autoimmune disorders, inflammatory diseases and cancer, today announced the online publication of a perspective in Cell Metabolism that highlights the rationale and potential of employing principles of immunometabolism to discover and develop novel medicines. The article, entitled The Untapped Opportunity and Challenge of Immunometabolism: A New Paradigm for Drug Discovery, was published online today in Cell Metabolism (DOI: 10.1016/j.cmet.2019.11.014).

Immune cells modulate their energy requirements in response to changes in their environment, which include interactions with pathogens, tumor cells, other immune system cells and molecules such as growth factors and antibodies. The metabolic programs that are induced or inhibited as immune cells respond to such stimuli can drive immune cell activation, differentiation, or suppression. Understanding the mechanisms through which metabolism can dictate the function or fate of immune cells is a new platform for target and biomarker discovery with a goal of identifying new medicines with potential to selectively tune the immune system to amplify or dampen its response. The perspective reviewed the underlying biology of immunometabolism and the new tools to discover and develop novel therapeutics based on this paradigm.

"To exploit this new field of immunometabolism, we have developed and industrialized a platform that comprehensively elucidates the metabolic pathways and targets with potential to control immune cell fate or function, as well as their associated metabolite biomarkers," said Laurence Turka, M.D., Chief Scientific Officer and co-founder of Rheos. "Our approach employs a proprietary integration of metabolomic, transcriptomic, and other data to generate immunometabolism network maps (imMAPs) that characterize immune cell activation and differentiation through a metabolic lens. Our imMAPs have potential to tap currently undiscovered or poorly understood biology and enable development of new therapeutics for a wide range of diseases including autoimmunity and cancer."

Barbara Fox, Ph.D., Chief Executive Officer of Rheos, added, "Immunometabolism has the potential to be the next frontier in drug discovery. Our pioneering product engine has the breadth and power to identify novel metabolic targets across a diverse set of pathways, better understand the metabolic impact of existing therapies and bring the benefits of personalized medicine to autoimmunity. Based on our work to-date, we have initiated drug discovery efforts in a number of programs and we look forward to providing further updates as we continue to make progress."

About Rheos Medicines

Rheos Medicines is a biopharmaceutical company harnessing insights in immunometabolism to develop novel therapeutics for patients with severe autoimmune disorders, inflammatory diseases and cancer. Our approach targets the underlying intracellular metabolism of immune cells and has the potential to unlock a new frontier in drug discovery for immune-mediated disease. Through a proprietary platform and product engine that integrates multiple "omic" datasets, we systematically define the biologic links between immune cell metabolism and function and simultaneously identify new drug targets and biomarkers of disease to bring precision to the treatment of immune-mediated diseases. We have assembled leading scientists whose discoveries opened the field of immunometabolism, clinicians with a deep understanding of immune-mediated diseases, and an experienced biotech leadership team. Rheos was founded by Third Rock Ventures and is located in Cambridge, MA. For more information, please visit http://www.rheosrx.com.

View source version on businesswire.com: https://www.businesswire.com/news/home/20191212005550/en/

Contacts

INVESTORS & MEDIA: Investors: Gad SofferChief Operating Officergsoffer@rheosrx.com 650-477-8183

John Grimaldi, Burns McClellanjgrimaldi@burnsmc.com 212-213-0006 x362

Media: Ryo Imai / Robert Flamm, Ph.D., Burns McClellanrimai@burnsmc.com / rflamm@burnsmc.com 212-213-0006 x315 / 364

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Rheos Medicines Announces Publication of Perspective in Cell Metabolism Highlighting the Rationale and Potential of Employing Principles of...

MORRISTOWN, N.J., Dec. 12, 2019 (GLOBE NEWSWIRE) -- BioAegis Therapeutics, Inc., a clinical stage company developing technology to address injurious inflammation while protecting immune function and vital organs in diseases driven by inflammation and infection, announces publication of new research findings with recombinant human plasma gelsolin in influenza. The research demonstrates that recombinant human plasma gelsolin therapy dramatically improves survival in a highly lethal influenza animal model.

Access Publication https://f1000research.com/articles/8-1860/v1

Findings Indicate That Plasma Gelsolin Supplementation Can Improve Influenza Outcomes

Seasonal influenza continues to be a cause of substantial morbidity and mortality. The US Center for Disease Control and Prevention (CDC) documented that seasonal influenza was responsible for close to 57,000 deaths during the 2018-2019 season. There is also concern that new strains could cause high death rates similar to past pandemics.

Studies conducted in collaboration with investigators at the Harvard T.H. Chan School of Public Health demonstrated clinical improvement in mice infected with lethal doses of influenza when administering gelsolin after a clinically relevant delay. The current FDA-approved antivirals target the flu virus, but do not address the severe later stage morbidity and mortality that that are the focus of plasma gelsolin (rhu-pGSN) therapy. Currently, resistance is also developing against the antivirals, which is why host-directed therapies are increasingly being sought for development.

Susan Levinson, PhD, Chief Executive Officer of BioAegis Therapeutics stated, Weve previously studied plasma gelsolin against multiple types of drug-sensitive and drug-resistant bacteria and this new data has demonstrated efficacy in influenza, a key viral pandemic threat. Each time we extend our studies with plasma gelsolin, we become even more persuaded of its potential to address serious medical needs where current therapy fails.

Research Presented at Recent Government Influenza Thought Leader Conference

Last month BioAegis was invited to participate in a workshop on REducing Pathogens After Influenza immune Response (repAIR) organized by the US Department of Health and Human Services BARDA (Biomedical Advanced Research and Development Authority), NIH (National Institute of Health) and ASPR (Assistant Secretary for Preparedness and Response). The conferences mission was to, Bring together thought leaders from multiple disciplines in medical research and clinical sciences who are interested in the study of host-based therapeutic interventions to provide more effective treatment of patients hospitalized with severe influenza.

Need for Host-directed Therapeutics Sought by Department of Health and Human Services

According to the Department of Health and Human Services, In the event of an influenza pandemic, or the annual seasonal epidemic, a therapeutic approved to treat individuals with late stage influenza disease could save tens to hundreds of thousands of lives. In addition, there is potential broad applicability of a host-based treatment to other infectious diseases.

Mark Dinubile, MD, Chief Medical Officer of BioAegis Therapeutics presented Plasma Gelsolin As Immunotherapeutic in Pneumonia including studies conducted by BioAegis Chief Scientific Advisor, Dr. Lester Kobzik at the Harvard TH Chan School of Public Health. The presentation highlighted the key finding -- plasma gelsolins unique ability to treat both viral and bacterial infections a pathogen agnostic approach.

While in Washington, D.C., Dr. Susan Levinson, CEO of BioAegis also presented this data at BARDAs TechWatch. BARDA has invested in many infectious threat programs, however, the space where pGSN is effective represents a gap in their portfolio.

About BioAegis Therapeutics

BioAegis Therapeutics Inc. is a clinical stage, private company whose mission is to exploit a key component of the bodys innate immune system to prevent adverse outcomes of diseases driven by inflammation and infection. BioAegis platform of opportunities exploits the multifunctional role of plasma gelsolin, a highly conserved, endogenous human protein.

Gelsolin has the potential to fill a major gap in the current treatment of inflammatory disease by controlling excess inflammation without suppressing the immune response to threats. In addition, recent findings demonstrate gelsolins unique pathogen agnostic approach its ability to treat both viral and bacterial infections.

In 2019, BioAegis successfully completed a Phase 1b/2a Community-Acquired Pneumonia clinical trial. BioAegis now is fundraising for its phase 2b trial in severe pneumonia. This study is designed to demonstrate gelsolin repletion reduces morbidity and mortality in severe pneumonia patients, a group that is at high risk for poor outcomes due to injurious inflammation.

This press release contains express or implied forward-looking statements, which are based on current expectations of management. These statements relate to, among other things, our expectations regarding managements plans, objectives, and strategies. These statements are neither promises nor guarantees but are subject to a variety of risks and uncertainties, many of which are beyond our control, and which could cause actual results to differ materially from those contemplated in these forward-looking statements. BioAegis assumes no obligation to update any forward-looking statements appearing in this press release in the event of changing circumstances or otherwise, and such statements are current only as of the date they are made.

For further information:

Steven Cordovano, 203-952-6373Email: scordovano@bioaegistx.comwww.bioaegistx.com

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BioAegis Therapeutics Announces Publication: "Delayed Administration of Recombinant Plasma Gelsolin Improves Survival in a Murine Model of Severe...

Chun-Jun Guo

Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA 94305, USA.Jill Roberts Institute for Research in Inflammatory Bowel Disease, Department of Medicine, Weill Cornell Medicine, NY 10021, USA.

Breanna M. Allen

Graduate Program in Biomedical Sciences, Departments of Otolaryngology and Microbiology and Immunology, Helen Diller Family Comprehensive Cancer Center, Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, CA 94143, USA.Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

Kamir J. Hiam

Graduate Program in Biomedical Sciences, Departments of Otolaryngology and Microbiology and Immunology, Helen Diller Family Comprehensive Cancer Center, Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, CA 94143, USA.Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

Dylan Dodd

Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Will Van Treuren

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

Steven Higginbottom

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

Kazuki Nagashima

Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA 94305, USA.

Curt R. Fischer

Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA 94305, USA.Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

Justin L. Sonnenburg

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

Matthew H. Spitzer

Graduate Program in Biomedical Sciences, Departments of Otolaryngology and Microbiology and Immunology, Helen Diller Family Comprehensive Cancer Center, Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, CA 94143, USA.Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

Michael A. Fischbach

Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA 94305, USA.Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.

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Depletion of microbiome-derived molecules in the host using Clostridium genetics - Science Magazine

CAR T-cell therapy has caused quite a stir in the immunotherapy world, but it is a process that requires precision and care. Quantitative polymerase chain reaction (qPCR) has thus far been the stalwart technique for providing a check on copy numbers, but here Ping Jin explains why droplet digital PCR (ddPCR) is more than a match for this technique.

CHIMERIC antigen receptor (CAR) T cells, first tested in cancer patients less than a decade ago,1 represent the latest generation of adoptive cell therapy and the most personalised approach to date. CAR T-cell therapy is a method of supercharging a patients immune system to fight their cancer and it involves three stages. First, T cells are isolated from a patients blood; then, using either viral vectors, transposon systems or mRNA transduction,2 T cells are genetically modified to express the CAR protein on their surface. Finally, the T cells are amplified in culture and infused back into the patient where they attack the cancer cells.

CAR T-cell therapy is rapidly gaining popularity as a specific method for treating cancer. According to clinicaltrials.gov, there are currently over 300 active or recruiting CAR T-cell therapy trials underway,3 mostly taking place in the US and China.4 According to one forecast, the global market for CAR T-cell therapies is expected to grow to $8 billion by 2028.5 However, since CAR T cells are a living therapy, as opposed to a synthetic drug, the process of preparing them to assure safety and effectiveness in patients is complex.

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Using droplet digital PCR to monitor the safety of CAR T cells - Drug Target Review

Trending News: Hypothyroidism Linked to Increased All-Cause Mortality in Patients 60 Years or Older

Two migraine prevention agents, cinnarizine and sodium valproate, were shown to be safe and effective in reducing incidence and severity of migraine within children and adolescents, according to the American Journal of Managed Care. In a randomized double-blind placebo-controlled trial including 149 Iranian pediatric and adolescent patients, patients were randomly assigned at 1:1:1 ratio to receive cinnarizine, sodium valproate, or placebo. Compared with placebo, the 2 preventive agents exhibited significant reductions in migraine incidence and severity, warranting further analyses into their efficacy among the global population.

New research indicates that hypothyroidism could be linked to increased all-cause mortality in patients aged 60 years and older, according to MD Magazine. An international team of researchers conducted a systematic review and meta-analysis of PubMed, Embase, Cochrane Library, Scopus, and Web of Science databases. Their findings indicate that patients aged 60 years or older with subclinical hypothyroidism (those who have a milder thyroid dysfunction) may not benefit from a treatment with synthetic thyroid hormone.

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Trending News: Hypothyroidism Linked to Increased All-Cause Mortality in Patients 60 Years or Older - Pharmacy Times

Using immunotherapy with genetically modified T cells that express chimeric antigen receptors or CARs designed to target tumor-associated molecules, have impressive efficacy in the treatment hematological malignancies.

A CAR is a synthetic construct that, when expressed in T cells, mimics T cell receptor activation and redirects specificity and effector function toward a specified antigen.[1]

In the treatment of cancer, this process is accomplished by linking an extracellular ligand-binding domain specific for a tumor cell surface antigen to an intracellular signaling module that activates T cells upon antigen binding.[1]

The presented studies include results from emerging second-generation cellular immunotherapy products that strive to overcome the limitations of existing products such as resistance and reduce toxicity and simplify treatment.

Cellular immunotherapy uses genetic engineering to enhance the ability of the immune system the bodys defense system against infection and disease to kill malignant cells in the blood, the bone marrow, and other sites, in order to keep cancer from coming back.

CAR T-cell TherapyChimeric antigen receptor T-cell therapies, better known as CAR T-cell therapies, are developed by harvesting a patients own T-cells, the immune systems primary cancer-killing cells, engineering them to target proteins specific to the surface of cancer cells, and reintroducing these modified T-cells back into the patients immune system to kill the cancer cells.

First generationFirst-generation CAR T-cell therapies primarily target CD-19, a protein found on the surface of most normal and malignant B cells in B cell cancers such as lymphoma. These therapies have been shown to produce long-term remissions in about one-third of patients with B-cell lymphomas that have not responded to prior therapies.

We are now seeing efforts to enhance the effectiveness of CAR T-cell therapy by designing products capable of attacking multiple targets, expand the availability of cellular immunotherapy to other blood cancers such as multiple myeloma and replace the complex manufacturing process required for CAR T-cell therapy with a uniform off-the-shelf product, noted Gary Schiller, MD, UCLA Health, an academic medical center which includes a number of hospitals and an extensive primary care network in the Los Angeles, California, region.

One of the phase I studies evaluates an off-the-shelf cellular immunotherapy product that targets two proteins found on the surface of lymphoma cells, including its potential to revive previously administered CAR T-cells that have stopped working.

Another study presents preclinical results for one of the first cellular immunotherapies to be based on off-the-shelf natural killer (NK) cells and the first, according to its manufacturer, to be genetically engineered to contain three active anti-tumor components.

The other two studies, also phase I studies, assess novel CAR T-cell therapies for multiple myeloma that test different dual-target strategies.

One investigational agent is genetically engineered to contain two proteins that attach to BCMA, a protein found almost exclusively on the surface of plasma cells, the immune-system cells that become cancerous in multiple myeloma.

The other is designed to target both BCMA and CD-38, another protein found on the surface of plasma cells. In both studies, many patients achieved minimal residual disease (MRD) negativity, which means that using highly sensitive testing fewer than one myeloma cell per 100,000 cells was identified in the bone marrow. Previous studies have shown that patients who achieve this milestone have a lower risk of relapse after more than three years of follow-up.

Dual-targeted CAR T-cell therapiesThe three phase I studies also hint at the possibility that dual-targeted CAR T-cell therapies might result in fewer patients experiencing moderate to severe cytokine release syndrome (CRS), a known adverse effect caused by an immune response in the body to the activated T cells that are attacking the cancer. CRS causes flu-like symptoms such as fever, body aches, and fatigue, and in severe cases can be life-threatening. Treatment with the drug tocilizumab can reduce CRS symptoms.

Dual-Targeted Antibody Elicits Durable ResponsesPatients with B-cell Non-Hodgkin Lymphoma (NHL) that had returned after or failed to respond to a median of three prior therapies showed complete responses (CR) and durable remissions after being treated with an investigational drug called mosunetuzumab (RG7828; Genentech/Roche). [2]

This investigational agent is a humanized, T-cell bispecific antibody designed to engage T cells and redirect their cytotoxic activity against malignant B cells. The drug works by activating the patients own T-cells, stimulating them to attack and kill cancerous B cells to which they have been introduced by the novel antibody.

Mosunetuzumab simultaneously binds to CD3 epsilon (CD3), a component of the T-cell receptor (TCR) complex, and to CD20, a B-cell surface protein expressed in a majority of B-cell malignancies. This results in crosslinking of the TCR, inducing downstream signaling events that leads to B-cell killing.

Among patients whose lymphoma progressed after treatment with CAR T-cell therapy, 22% had complete remissions when treated with mosunetuzumab. This new drug targets two proteins, one on the surface of tumor cells and the other on the surface of the recipients Tcells.

Unlike CAR T-cell therapy, mosunetuzumab is an off-the-shelf immunotherapy product that can be given to patients without having to genetically modify their T cells, noted lead author Stephen J. Schuster, MD, of Abramson Cancer Center at the University of Pennsylvania in Philadelphia.

Mosunetuzumab generates long-lasting responses with a very tolerable safety profile in patients with B-cell non-Hodgkin lymphomas for whom multiple prior treatments have failed and whose prognosis is poor. Of particular interest, we are seeing durable complete remissions in patients whose lymphomas progressed after CAR T-cell therapy, he added.

The researchers observed many remissions continue after patients stop receiving the drug.

I have stopped therapy in some patients after six months and they have remained in remission. Some patients have remained in remission without additional therapy for more than a year, Schuster said.

New treatment options are needed not only for patients in whom CAR T-cell therapy has failed, but also for those patients whose lymphomas are getting worse so quickly that they cannot wait for CAR T-cell manufacturing, which takes several weeks, Schuster explained.

The data presented during the annual meeting of the American Society of Hematology included 270 patients (median age 62, 172 men) enrolled in the phase I trial in seven countries (the United States, Australia, Canada, Germany, South Korea, Spain, and the United Kingdom). All participating patients had B-cell lymphomas that had come back or not responded to a median of three prior therapies. Two-thirds of patients (67%) had fast-growing lymphomas; 85 (31%) patients had more slow-growing forms of the disease. In 30 patients (11%), the cancer was resistant to or returned after an initial response to CAR T-cell therapy; in 77 patients (29%), the disease had progressed after a stem cell transplant.

All patients were treated with mosunetuzumab by intravenous infusion. They had an imaging test at either six weeks or three months after starting therapy to assess the initial response to treatment, and responses continued to be followed every three months thereafter.

Forty-six of 124 patients with fast-growing lymphomas (37%) had measurable decreases in the extent of their cancer (objective response); 24 of 124 patients (19%) saw all detectable tumors disappear (complete response). A higher response rate was observed in patients with higher exposure to mosunetuzumab. Among patients with slow-growing lymphomas, 42 of 67 (63%) had objective responses and 29 of 67 (43%) had complete responses. Both objective response rate and complete response rate were maintained in subgroups of patients at high risk for relapse.

Complete remissions appear to be long lasting, Schuster said.

With a median follow-up of six months since first complete remission, 24 of 29 patients (83%) who achieved complete remissions of their slow-growing lymphomas and 17 of 24 patients (71%) who achieved complete remissions of their fast-growing lymphomas remain free of disease. In some patients whose cancers progressed after receiving CAR T-cell therapy, highly sensitive molecular testing showed that the previously administered CAR T cells increased in number.

This suggests that, in addition to its ability to kill cancerous B cells, mosunetuzumab may also help augment the effect of the prior CAR-T treatment, Schuster noted.

Cytokine-release syndromeIn this study, 29% of patients treated with mosunetuzumab experienced cytokine-release syndrome that was mostly mild.

Cytokine release syndrome or CRS is caused by a large, rapid release of cytokines into the blood from immune cells affected by the immunotherapy. While most patients have a mild reaction, sometimes patients may have a severe, life threatening, reaction.

In 3% of patients, CRS was treated with tocilizumab (Actemra; Genentech/Roche). Four percent of patients experienced moderately severe neurologic side effects. Patients who received higher doses of mosunetuzumab were no more likely to have CRS or neurologic side effects than patients treated at lower doses.

A study of a higher dose of mosunetuzumab is now enrolling patients and long-term follow-up of these patients will ultimately help to better evaluate the durability of response data.

Larger, randomized trials are needed to further confirm these promising data and determine whether the treatment benefit of mosunetuzumab is enhanced when it is used earlier in the course of lymphoma therapy or in combination with other agents, Schuster concluded.

Novel Off-the-Shelf CARPreclinical studies provide the first evidence that cellular immunotherapy for B cell cancers could ultimately become an off-the-shelf product, capable of being uniformly manufactured in large quantities as prescription drugs are.

We have taken the concept of traditional pharmaceutical drug development and applied it to cellular therapy, explained senior author Bob Valamehr, Ph.D, of Fate Therapeutics, a San Diego biopharmaceutical company.

The product called FT596, is among the first cellular immunotherapies to be based on off-the-shelf NK cells the first line of defense of the immune system and is the first cellular immunotherapy to be genetically engineered to contain three active anti-tumor components, Valamehr explained.

Comparable with standard CAR T-cell therapyFT596 demonstrated comparable ability to kill cancerous white blood cells as standard CAR T-cells and, when combined with the drug rituximab (Rituxan; Genentech/Roche), killed cancerous white blood cells that were no longer responding to standard CAR T-cell therapy due to loss of the CD19 antigen target.

The U.S. Food and Drug Administration (FDA) approved Fate Therapeutics Investigational New Drug Application for FT596 in September 2019 and the company hopes to begin a first-in-human phase I clinical trial for the treatment of B-cell lymphoma and chronic lymphocytic leukemia in the first quarter of 2020.

The primary purpose of this trial will be to assess the safety and activity of FT596 in patients.

ManufacturingThe development and manufacturing of FT596 begins with human induced pluripotent stem cells (iPSCs) that are uniquely capable of unlimited self-renewal and can differentiate into more than 200 types of human cells. These iPSCs are genetically engineered, after which a single genetically engineered cell or clone is selected and multiplied in the laboratory to create a master engineered cell line that can be repeatedly used to generate cancer-fighting immune-system cells such as NK and T cells.

Natural Kiler Cells or NK cells are a type of lymphocyte and a component of innate immune system, the bodys first line of defense against infection and disease. Unlike T-cells, which have to be trained to recognize their target and can kill only cells that display that target on their surface, NK cells do not need special preparation before going on the attack and can kill many different types of transformed or infected cells.

NK cells are multifaceted and can be viewed as a jack-of-all-trades when it comes to protecting the host, whereas T cells can act in only one way, Valamehr explained.

But NK cells are also different in other ways. They are inherently limited in their capacity to multiply and expand when infused into patients, and they have a shorter lifespan.

Valamehr and his colleagues used genetic engineering to address these shortcomings. In addition to engineering FT596 to carry a CAR targeting the CD19 protein, which is produced by nearly all B-cell lymphomas and leukemias, they inserted two other novel proteins: CD16, which boosts and broadens the NK cells ability to kill cancer cells, and IL15, which stimulates FT596 to proliferate and persist.

Valamehr explained that FT596 has been designed to address two more limitations of CAR T-cell therapy .

The investigational agent is an off-the-shelf product. As a result, it significantly improves the current patient-by-patient CAR T-cell treatment paradigm by eliminating the time-consuming and costly process that is currently required to treat a patient with CAR T-cells.

The addition of the CD16 protein gives FT596 broader therapeutic activity and versatility. In combination with rituximab, FT596 has the potential to lead to deeper and more durable responses and overcome resistance that hampers the long-term efficacy of CAR T-cell therapy.

Eliminating the high production cost, weeks of manufacturing time, and complex manufacturing process required for CAR T-cell therapy and replacing it with a mass-produced, off-the-shelf product, promises to expand access to effective cell-based cancer immunotherapy to many more patients who may benefit from it, Valamehr concluded.

Results from CARTITUDE-1 in R/R Multiple MyelomaPatients with multiple myeloma who had received a median of five prior therapies, and for whom standard-of-care treatments were no longer working, had a high response rate when treated with the investigational CAR T-cell therapy JNJ-68284528 (JNJ-4528), which targets BCMA, a protein commonly found on the surface of multiple myeloma cancer cells.

These patients participated in a clinical trials (NCT03548207), supported by Janssen Research & Development, designed to characterize safety of and establish the recommended Phase II dose (RP2D) (Phase Ib) and to evaluate the efficacy of JNJ-68284528 (Phase II).

We are seeing a high response rate, with most patients achieving MRD negativity, noted lead study author Deepu Madduri, MD, of The Tisch Cancer Institute at Mount Sinai in New York.

Considering these patients have all received multiple prior therapies, these results are extremely encouraging, Madduri added.

All evaluable patients receiving this CAR T-cell therapy have achieved MRD-negative disease state and 27 of 29 patients are progression free at a median follow-up of six months, Madduri said.

Multiple myeloma is a cancer of plasma cells, which are found in the bone marrow and are part of the immune system, the bodys defense system against infection. Typical signs and symptoms of multiple myeloma may be bone pain or fractures, high levels of calcium in the blood, kidney damage, and anemia. Multiple myeloma affects an estimated 160,000 people each year, occurs most often in people over 60. The disease is slightly more common in men than in women.

Although new therapies for multiple myeloma have recently become available that can extend patients life expectancy, a cure for the disease remains elusive.

We can get the disease into remission, but most patients unfortunately relapse, and outcomes are very poor for patients who have relapsed multiple times, she said.

Researchers explained that JNJ-4528 is a novel CAR T-cell therapy featuring two molecules that bind to BCMA, a protein found on the surface of multiple myeloma cells.

We are learning that every CAR T-cell therapy is different, Madduri said.

JNJ-4528 has a unique CAR T-cell composition in patients, preferentially enriched in CD8 T cells, which are believed to be one of the most important T cells in killing cancer cells, she noted.

This phase Ib/II trial is continuing to enroll patients.

During the 2019 annual meeting of the American Society of Hematology, Madduri reported results for the first 29 patients enrolled.

Patients T-cells were collected and sent to a laboratory where they were genetically engineered to express JNJ-4528. Prior to re-infusing these CAR T-cells, the patients received three days of chemotherapy to make room in their immune systems for the engineered T-cells.

Following chemotherapy, each patient received a single infusion of the JNJ-4528 CAR T-cells.

After a minimum of 28 days, these patients had blood and bone marrow exams, which was followed by exams at six months, and one year after treatment to assess their response. The primary aims of the trial are to assess the therapys safety and to confirm the dose to be tested in a larger, phase II trial.

The median follow-up time in the current analysis is six months. Overall, 100% of patients had a clinical response to JNJ-4528. Moreover, 66% had a stringent complete response, meaning that sensitive laboratory and microscopic tests found no evidence for myeloma proteins or cells in blood, urine, or bone marrow.

Most patients (93%) experienced some form of CRS. One patient had severe (grade 3) CRS, and one patient died from its complications 99 days after the CAR T-cell infusion. In 76% of patients, CRS was treated with tocilizumab.

To see some patients in this heavily pretreated population surviving for a year or more with a one-time treatment and a manageable safety profile is remarkable, Madduri explained.

These patients feel that they have their quality of life back. They no longer have to come into the clinic for weekly treatments and some are well enough to travel, Madduri concluded.

The phase II portion of this study is ongoing to evaluate the overall response rate of patients treated with JNJ-68284528 (JNJ-4528). Additional clinical studies are evaluating the safety and efficacy of JNJ-4528 in different multiple myeloma treatment settings.

BreakthroughEarlier this week the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for JNJ-68284528 (JNJ-4528).

The granting of Breakthrough Therapy Designation for JNJ-68284528 (JNJ-4528) is a significant milestone as we continue to accelerate the global development of this innovative CAR-T therapy in collaboration with Legend Biotech, noted Sen Zhuang, MD, Ph.D., Vice President, Oncology Clinical Development, Janssen Research & Development.

We look forward to continuing to work closely with the U.S. Food and Drug Administration to advance the clinical development program for JNJ-68284528 (JNJ-4528) and ultimately bring this BCMA-targeted immunotherapy to patients living with multiple myeloma who are in need of a new therapeutic option, Zhuang concluded.

Encouraging Results for Dual-Targeted CAR T-Cell TherapyMore than three out of four patients with multiple myeloma that returned or did not respond to at least two therapies remained in remission seven months after treatment with a novel CAR T-cell therapy targeting two proteins that are frequently found on myeloma cells.

Nine patients experiencing sustained remissions in this study, which ws supported by the National Natural Science Foundation of China, the Major Technological Innovation Special Project fund of Hubei Province of China, and Cellyan Therapeutics, were diagnosed with a difficult-to-treat form of multiple myeloma in which the disease has spread beyond the bone marrow.

Roughly one in 10 patients with multiple myeloma develop tumors in the organs or soft tissues such as the blood vessels, muscles, and nerves. These so-called extramedullary tumors respond poorly to treatment, and patients who develop them have a poor outlook and poor health related quality of life (hrQoL)

Our results show that this CAR T-cell product can effectively achieve elimination of extramedullary tumors, said study author Yu Hu, MD, Ph.D, of Union Hospital, Huazhong University of Science and Technology in Wuhan, China.

Although these are preliminary data, they are encouraging for patients with multiple myeloma who have not responded to other therapies, Hu added.

Hu and his colleagues are developing the first CAR T-cell therapy to be genetically engineered to target BCMA and CD38, two proteins found on the surface of plasma cells. Multiple myeloma is a cancer of plasma cells, which are found in the bone marrow and are part of the immune system, the bodys defense system against infection and disease.

Our thinking was that targeting both of these proteins would improve treatment efficacy without increasing toxicity, and induce deeper, more durable remissions, Hu noted.

The first-in-humans phase I trial enrolled 22 patients whose average age was 59, of whom 11 were men. All had multiple myeloma that had returned or not responded to at least three therapies. Nine of the 22 patients had extramedullary tumors. The study aims were to determine the safest and most effective dose of the CAR T-cell therapy as well as to initially evaluate its effectiveness.

Just like in other trials with CAR T-cell therapies, the participating patients received three days of chemotherapy to make room in their immune systems for the engineered T-cells. Then each patient was infused with the dual-targeted CAR T cells. Patients were divided into five groups, with each group receiving a higher dose than the previous one. Depending on the cell dose, patients received either one or two infusions.

At a median of 36 weeks of follow-up, 18 patients (90.9%) had MRD-negative disease. Twelve patients (54.5%) had a stringent complete response, meaning that no plasma cells were detected in the bone marrow. Seven patients (31.8%) had a good or very good partial response, meaning that the level of M-protein (an abnormal protein produced by cancerous plasma cells) in the blood or urine was reduced but still detectable. In eight of the nine patients with extramedullary lesions, these tumors were undetectable on their computed tomography scans. For the 17 patients who remained in remission at seven months after treatment, the median duration of response was 28.8 weeks.

The adverse events observed included 20 patients who experienced CRS, of whom six needed treatment. No serious adverse neurologic effects such as seizures, movement impairment, difficulty speaking or understanding speech, or fatal swelling in the brain were reported.

With this dual-targeted CAR T-cell therapy, we have demonstrated a high response rate, especially a higher rate and longer duration of stringent complete response, compared with other therapies, as well as effective elimination of extramedullary lesions, with no serious neurologic adverse effects and manageable levels of other adverse effects, Hu concluded.

The investigators continue to follow the patients for the next two years. They are also planning to conduct a phase II trial in both China and the United States to test the treatments effectiveness in a larger number of patients.

Clinical trialsA Study of JNJ-68284528, a Chimeric Antigen Receptor T Cell (CAR-T) Therapy Directed Against B-Cell Maturation Antigen (BCMA) in Participants With Relapsed or Refractory Multiple Myeloma (CARTITUDE-1) NCT03548207

References[1] Srivastava S, Riddell SR. Chimeric Antigen Receptor T Cell Therapy: Challenges to Bench-to-Bedside Efficacy. J Immunol. 2018;200(2):459468. doi:10.4049/jimmunol.1701155 [Abstract][2] Schuster SJ, Bartlett NL, Assouline S, Yoon SS, Bosch F, Sehn LH, Cheah CY, Shadman M, et al. Mosunetuzumab Induces Complete Remissions in Poor Prognosis Non-Hodgkin Lymphoma Patients, Including Those Who Are Resistant to or Relapsing After Chimeric Antigen Receptor T-Cell (CAR-T) Therapies, and Is Active in Treatment through Multiple Lines. 61st annual meeting of the American Society of Hematology. Program: General Sessions. Session: Plenary Scientific Session. Hematology Disease Topics & Pathways: antibodies, Follicular Lymphoma, CRS, Diseases, Biological, Therapies, neurotoxicity, Adverse Events, CAR-Ts, Non-Hodgkin Lymphoma, DLBCL, immunotherapy, Lymphoid Malignancies. [Abstract][3] Goodridge JP, Mahmood S, Zhu H, Gaidarova S, Blum R, Bjordahl R, Cichocki F, et al. FT596: Translation of First-of-Kind Multi-Antigen Targeted Off-the-Shelf CAR-NK Cell with Engineered Persistence for the Treatment of B Cell Malignancies. 61st annual meeting of the American Society of Hematology. Program: Oral and Poster Abstracts. Type: Oral. Session: 625. Lymphoma: Pre-ClinicalChemotherapy and Biologic Agents: Targeting Apoptosis Pathways in Lymphoma.[Abstract][4] Madduri D, Usmani SZ, Jagannath S, Singh I, Zudaire E, Yeh TM, Allred AJ, Banerjee A, et al. Results from CARTITUDE-1: A Phase 1b/2 Study of JNJ-4528, a CAR-T Cell Therapy Directed Against B-Cell Maturation Antigen (BCMA), in Patients with Relapsed and/or Refractory Multiple Myeloma (R/R MM). 61st annual meeting of the American Society of Hematology. Program: Oral and Poster Abstracts. Type: Oral Session: 653. Myeloma: Therapy, excluding Transplantation: Novelty in CAR T in Relapsed/Refractory Multiple Myeloma. [Abstract][5] Li C, Mei H, Hu Y, Guo T, Liu L, Jiang H, Tang L, Wu Y, et al. A Bispecific CAR-T Cell Therapy Targeting Bcma and CD38 for Relapsed/Refractory Multiple Myeloma: Updated Results from a Phase 1 Dose-Climbing Trial61st annual meeting of the American Society of Hematology. Program: Oral and Poster Abstracts. Type: Oral. Session: 653. Myeloma: Therapy, excluding Transplantation: Novel Therapy for Relapsed Myeloma. Hematology Disease Topics & Pathways: Biological, Diseases, Adult, Therapies, Lymphoma (any), Adverse Events, CAR-Ts, Elderly, Biological Processes, Technology and Procedures, Cell Lineage, Study Population, Clinically relevant, Lymphoid Malignancies.

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ASH 2019: Second-gen CAR T-Cell Therapy Overcome Resistance, Reduce Toxicity and Simplify Treatment - OncoZine

The cornerstone of managing any disease, especially the complicated ones like diabetes, is early diagnosis and access to treatment. In case of this hormonal disorder, early diagnosis is extremely essential because it is like to affect your immune function badly. According to a study by Case Western Reserve University School of Medicine in Cleveland, uncontrolled diabetes makes it difficult for people affected by the condition to avoid infections. High sugar levels in their blood can unleash destructive molecules that interfere with the bodys natural infection-control mechanism, says the study.

When your your blood sugar levels go for a toss, every cell of your body gets severely damaged. In fact, diabetes can affect your crucial organs too. These damages drive your body into an immune response mode leading to inflammation. Prolonged inflammation leads to various kinds of diseases including obesity.

In case of excessive cell and tissue damage in your body, the immune cells are likely to go on an overdrive mode. Under normal circumstances, the macrophages (white blood cells which are part of your immune system) clear the cellular debris to battle any kind of tissue damage. They also wipe out foreign substances, microbes, cancer cells, and everything else that arent healthy to body cells. When there is too much damage happening and that too for a prolonged period of time, the macrophages go on an overdrive and kill the healthy cells leading to inflammation. That is why you need to keep your blood sugar levels in check, if you need a healthy immune system.

Your bodys natural defence mechanism needs to be taken care of, so that it doesnt go weak. The best way to do so is having the right foods and exercising regularly. Having ayurvedic herbs and formulas will also go a long way in revving up your immune system. Heres a list of foods and formulas to keep you strong through these winter days.

Dabur has long been using the wisdom of Ayurveda through its formulas to give us effective, natural, side-effect-free solutions for conditions that are tough to treat. Dabur Sugar-Free Chawanprakash is the best example of such an ayurvedic remedy. This all-natural product, made from more than 45 trusted Ayurvedic ingredients like Amla, Ashwagandha, Guduchi etc., modulates the activity of natural killer cells and cytokines to strengthen your bodys defence mechanism. Amla, which is an extremely rich source of Vitamin C, helps in amping up immunity. Chyawanprakash reduces the activation of a complement pathway which gets activated in case of an allergic inflammation, damaging the surrounding cells. It also increases the activity of immune cells called macrophages. These cells play a role in triggering non-specific immune responses and further reduce chances of infections. Apart from this, Dabur Chawanprakash comes with a plethora of other health benefits: Boosting your respiratory and brain functions functions, revving up your heart health and helping you look younger.

Packed with vitamin E and unsaturated fatty acids like omega-3 fats, include avocado in the form of salad or along with banana (mash one banana and one avocado) to attain its benefits. You can even use it in desserts.

Starting your day with a bowl of oats porridge or oats upma is a good idea, not only because it will fill you up but will boost your immunity and metabolism as well. Oats is rich in fibre and vitamin B12, which plays a key role in boosting immunity and lowering your risk of infections.

They are not only a perfect option to up your energy and satiate your hunger pangs, but also play a key role in strengthening your immunity. Eat 23 figs or walnuts in a day to increase your intake of potassium, zinc, iron and unsaturated fats, which improve your overall health. If you dont like nuts, make chikki or add them in oats or milk for effective results.

It is rich in probiotics, a kind of bacteria which fight infections. Including it in the diet not only aids in digestion but also improves immunity, lowering your risk of infections. Make sure you eat at least a small bowl of curd per day either in the form of buttermilk, raita or hung curd to boost immunity.

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Published : December 9, 2019 3:50 pm | Updated:December 9, 2019 5:40 pm

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Dont let diabetes take a toll on your immunity: Bolster it with natural remedies - TheHealthSite

Eating a very low-calorie diet is an unpleasant but effective way to live longer, prevent age-related diseases and even improve the immune systems function. A new study in mice finds that a compound used in herbal medicine can give a similar immune boost if given before vaccination no dieting required.

Ina new paper inScience Signaling, researchers at the University of Hyderabad in India and Cornell University College of Veterinary Medicine show that a compound called halofuginone improves the immune response to a potential vaccine against dengue virus. Halofuginone tricks the body into thinking it is starving for amino acids, which activates a pathway that results in more, and better, antibodies that are better able to neutralizing the virus. With additional testing, the compound could be part of a strategy to improve the effectiveness of vaccines for diseases such as dengue, which have been difficult to control.

Avery August

The research group was led by Avery August, vice provost for academic affairs and Howard Hughes Medical Institute professor of immunology, and included graduate students Sabrina Solouki and Jessica Elmore, in collaboration with Weishan Huang, adjunct assistant research professor of Microbiology and Immunology, and Nooruddin Khan, assistant professor of biotechnology at the University of Hyderabad in India.

From previous studies, they knew that halofuginone activates a pathway called the amino acid starvation response, which normally kicks in when the body is starved of proteins. Restricting calories can have multiple impacts on the immune system, and the researchers wanted to know how artificially activating this pathway would affect immune response to a vaccine.

Weve been studying the pathway using a compound called halofuginone, which is a natural product found in plants, August said. Halofuginone is a component of an herb used in Chinese medicine. It shows potential for treating muscular dystrophy, autoimmune disease and certain cancers and appears to have few side effects. It mimics amino acid starvation in the body by blocking the enzyme that links amino acids to the molecules that deliver them to the site of protein production.

Members of Augusts lab have been experimenting with different mixes of dengue proteins to develop a better vaccine, so dengue was a natural choice for testing the immune effects of halofuginone. The World Health Organization lists dengue among its top 10 threats to global health and about half the worlds population is at risk of contracting the virus. It is transmitted by mosquitoes and causes flu-like symptoms in most people, but in about 20 percent of cases, the infection progresses into severe dengue, which can cause shock, hemorrhaging or death.

The virus has been especially difficult to control, in part, because there is no vaccine suitable for individuals who have not already been exposed. A vaccine developed by Sanofi and tested in the Philippines in 2017 successfully protected individuals who had already been exposed to the virus, but increased the risk of severe dengue in previously unexposed children. Currently, the pharmaceutical company Takeda is testing a new dengue vaccine in a multi-country clinical trial. Initial results are promising, but it is unknown whether the new vaccine will also increase the risk of severe dengue in unexposed individuals.

In the current study, researchers injected some mice with halofuginone and some with an innocuous salt solution, then inoculated all of the mice with a potential dengue vaccine. Then they looked for differences in the immune response to the vaccine in the two groups.

Mice that received halofuginone produced twice as many antibodies against the virus compared to mice that only received the vaccine, and these antibodies bind to dengue viral components more strongly. Mice dont contract dengue, so the researchers couldnt test whether they were protected. But when they tested the efficacy of the antibodies against dengue virus in a test tube, they saw that halofuginone resulted in antibodies that more effectively neutralized the virus. We were particularly surprised by the quality of the antibody response which is the important part, August said. In this case the actual affinity of the antibodies for the virus particles was enhanced by the halofuginone.

Furthermore, the researchers showed that halofuginone works specifically by encouraging the formation of germinal centers in the lymph nodes and spleen. Germinal centers act like factories to produce the B cells that pump out antibodies, and memory B cells that persist for decades and restart antibody production if the invader returns.

This pathway hasnt before been thought of as one that can regulate enhancing vaccine memory, said August. It allows us potentially to enhance the bodys memory specifically for that vaccine.

Halofuginone worked equally well to enhance the immune response against the four types of dengue virus, but this approach likely would boost any vaccine.

Of course, before a shot of halofuginone becomes part of a standard vaccine regimen, the compound will need to be further tested for safety and effectiveness in humans. These experiments used doses of halofuginone that are larger than what people typically ingest through herbal medicine practices. Additionally, the researchers have not yet screened for side effects on other organ systems in the mice, but plan to explore this area in the future.

This study primarily focused on B cells that produce antibodies against invading pathogens, but now Augusts group and their collaborators are examining the specific effects of halofuginone on the response of T cells, which detect the presence of invaders, kill infected cells and signal B cells to create antibodies.

Overall, the findings suggest that investigating drugs that mimic starvation may be a promising area of research for finding strategies to enhance vaccine effectiveness, especially for dengue and other diseases that still lack approved vaccines.

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Simulating amino acid starvation may result in better vaccines for dengue and other infections - Jill Lopez

The symbiotic relationship between host and microbes starts early in life and is important not only in terms of how the neonate microbiome ultimately develops, but also its potential impact on long-term infant health.

A current ongoing debate within the scientific community is whether gut colonization starts during pregnancy or at birth. Indeed, the crucial question of when bacteria first colonize the body has yet to be answered.

Microbial transfer at the feto-maternal interface

For long time, prevailing scientific dogma stated that neonates are born sterile and only upon delivery are they populated by microorganisms. For instance, in 1900, French pediatrician Henry Tissier declared: The fetus lies in a sterile environment.

Things changed in 1982, however, when a study found bacteria in the placenta. That discovery prompted scientists to accurately corroborate these findings.

By using both conventional culturing techniques and 16S ribosomal RNA gene and/or metagenomic sequencing in animal studies and humans in the mid-2000s, bacteria were also detected in what had been presumed to be sterile tissue from healthy term neonates. These included the placenta, amniotic fluid and meconium.

Contrary to initial belief, therefore, the evidence of bacterial presence in fetal membranes and in newborns first stool would not necessarily be a sign of infection. Furthermore, no distinction is made in this regard between premature infants and matched controls, which, in turn, might support the existence of a placenta microbiome in healthy pregnancies.

Other species such as clams, tsetse flies and turtles appear to inherit a mothers microbiome before birth. It is therefore no surprise that humans may also have microbes in utero.

Major caveats remain, however, making it difficult to prove the existence of a fetal-maternal microbiome. For instance, it is unclear which route microbes use to enter the intrauterine space, with their origin thought to be the mother. Furthermore, scientists leading this field remain uncertain about whether the organisms are viable or if free DNA is being detected, and it is unclear to what extent those bacteria are temporary passengers of the fetus or indeed residents in the fetal gut.

Contamination of the samples is also plausible. To tackle this issue, scientists have recently provided evidence of fetus exposure to bacterial DNAit remains unclear whether this originates from viable or dead bacteriaand metabolites prior to birth beyond the level of background contamination.

How the transfer of commensal organisms from the maternal gut to blood and systemic locations mechanistically occurs has been largely explored in mice, showing that maternal gut microorganisms migrate to various locations, including the mammary gland via an endogenous cellular route (called the bacterial entero-mammary pathway), taking place mainly during late pregnancy and lactation. These findings suggesting that transporting bacterial components from the gut to both blood and breast milk cells is possible, probably in the form of non-viable bacteria vectorized by immune cells, was formerly proposed from a study in mother-infant pairs. As such, this could program the neonatal immune system to better tackle the challenge of sorting out pathogens and commensal organisms.

There is also evidence of the impact on offspring development of symbiotic interactions between the mother and gut microbiome. In this regard, Elaine Hsiao and colleagues showed that injecting pregnant dams with a mock virus yielded offspring that exhibited autism-like symptoms. Such behavioral abnormalities in the offspring of maternal immune activation in mice were accompanied by defects in intestinal integrity and alterations in gut microbiota composition.

From an evolutionary perspective, it has been hypothesized that microbes may have influenced host sociability and behavior through the known microbiota-gut-brain axis as a way to propagate their own genetic material.

Other host-related and environmental factors such as maternal obesity and weight gain and exposure to environmental factors such as a high-fat diet and non-nutritive sweeteners may also affect infant microbial colonization and health programming later in life.

Thus, gut colonization during the perinatal period, especially during the first 2 to 3 years of life, is influenced by multiple biological and environmental factors and provides a window of opportunity to potentially reduce the risk of chronic diseases in childhood and later life.

Birth as the major microbial encounter

Although data exists regarding gut colonization before birth, some scientists remain skeptical and argue that the presence of bacterial DNA in presumably sterile fetal tissues such as the placenta does not lead to the establishment of the seed of the human microbiome before birth.

It is widely accepted that humans first exposure to microbes occurs in the birth canal. After delivery, maternal peripheral blood mononuclear cells and human breast milk cells contain the genetic material of a wide range of gut microbes, some of which are also found in infant feces.

At birth, newborn babies experience rapid colonization by microbes from their mothers and the surrounding environment. Delivery type is a critical factor involved in establishing the infant gut microbiota. Epidemiological studies indicated that cesarean section birth may come with a slightly increased risk of developing allergies and later obesity. Recent research has revealed that, compared with vaginal delivery, cesarean sections may predispose individuals to opportunistic infections.

Scientists have found no differences in the bacterial DNA recovered from placenta samples (of preterm infants and those of babies born at term) from that found on commercial reagents. Therefore, given that the placenta has a low bacterial biomass, it is also plausible that the bacterial DNA identified may derive from contamination through dust or commercial reagents.

More recently, an analysis of placental samples from more than 537 women, with either complicated or uncomplicated pregnancies, showed that the placenta was unlikely to be the major source of the infant microbiota. An experimental approach consisting of the use of two different kits for DNA extraction and different molecular methods to detect bacterial DNA allowed to reduce the chance of false-positive results due to contamination. The fact that almost 5% of placenta samples collected before labour contained group B Streptococci, a major cause of sepsis in newborns, also reveals that bacterial infection of the placenta is not a frequent cause of adverse pregnancy outcome.

Meanwhile, the observation of a handful of microbes in the placenta, umbilical cord blood, amniotic fluid and meconium does not necessarily support the existence of a complex microbiome, like the ones found in other niches such as the gut or saliva. As with the study of the breast milk microbiome, characterizing microorganisms colonizing the fetus prior to birth requires sophisticated methodologies that distinguish resident microbes from those that temporarily colonize the sample.

On the whole, it is clear that host interaction with intestinal microbes either during pregnancy or during the immediate postnatal period may have a profound impact on the neonatal microbiome and health and disease in later life by programming immune and metabolic pathways. Compensating for the lack of exposure to maternal microbes upon cesarean section delivery by a simple gesture might prove beneficial. Targeting the development of host-microbes symbiosis in early life might also be considered as a means of preventing the uncontrolled rise in incidence of chronic diseases that current medicine is not able to cure.

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Kovalovszki L, Villnyi Z, Pataki I, et al. Isolation of aerobic bacteria from the placenta. Acta Paediatr Acad Sci Hung. 1982; 23(3):357-60.

Aagaard K, Ma J, Antony KM, et al. The placenta harbors a unique microbiome. Sci Transl Med. 2014; 6(237):237ra65. doi: 10.1126/scitranslmed.3008599.

Collado MC, Rautava S, Aakko J, et al. Human gut colonisation may be initiated in utero by distinct communities in the placenta and amniotic fluid. Sci Rep. 2016; 6:23129. doi: 10.1038/srep23129.

Jimnez E, Marn ML, Martn R, et al. Is meconium from healthy newborns actually sterile? Res Microbiol. 2008; 159(3):187-93. doi: 10.1016/j.resmic.2007.12.007.

Mshvildadze M, Neu J, Shuster J, et al. Intestinal microbial ecology in premature infants assessed using non-culture based techniques. J Pediatr. 2010; 156(1):20-5. doi: 10.1016/j.jpeds.2009.06.063.

Funkhouser LJ, Bordenstein SR. Mom knows best: the universality of maternal microbial transmission. PLoS Biol. 2013; 11(8):e1001631. doi: 10.1371/journal.pbio.1001631.

Stinson LF, Boyce MC, Payne MS, Keelan JA. The not-so-sterile womb: evidence that the human fetus is exposed to bacteria prior to birth. Front Microbiol. 2019; 10:1124. doi: 10.3389/fmicb.2019.01124.

Rodrguez JM. The origin of human milk bacteria: is there a bacterial entero-mammary pathway during late pregnancy and lactation? Adv Nutr. 2014; 5(6):779-84. doi: 10.3945/an.114.007229.

Hsiao EY, McBride SW, Hsien S, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell. 2013; 155(7):1451-63. doi: 10.1016/j.cell.2013.11.024.

Sherwin E, Bordenstein SR, Quinn JL, et al. Microbiota and the social brain. Science. 2019; 366(6465). doi: 10.1126/science.aar2016.

Garcia-Mantrana I, Collado MC. Obesity and overweight: impact on maternal and milk microbiome and their role for infant health and nutrition. Mol Nutr Food Res. 2016; 60(8):1865-75. doi: 10.1002/mnfr.201501018.

Wankhade UD, Zhong Y, Kang P, et al. Maternal high-fat diet programs offspring liver steatosis in a sexually dimorphic manner in association with changes in gut microbial ecology in mice. Sci Rep. 2018; 8:16502. doi:10.1038/s41598-018-34453-0.

Olivier-Van Stichelen S, Rother KI, Hanover JA. Maternal exposure to non-nutritive sweeteners impacts progenys metabolism and microbiome. Front Microbiol. 2019; 10:1360. doi: 10.3389/fmicb.2019.01360.

Rodrguez JM, Murphy K, Stanton C, et al. The composition of the gut microbiota throughout life, with an emphasis on early life. Microb Ecol Health Dis. 2015; 26. doi: 10.3402/mehd.v26.26050.

Perez PF, Dor J, Leclerc M, et al. Bacterial imprinting of the neonatal immune system: lessons from maternal cells? Pediatrics. 2007; 119(3):e724-32. doi: 10.1542/peds.2006-1649.

Shao Y, Forster SC, Tsaliki E, et al. Stunted microbiota and opportunistic pathogen colonization in caesarean-section birth. Nature. 2019; 574(7776):117-21. doi: 10.1038/s41586-019-1560-1.

Lauder AP, Roche AM, Sherrill-Mix S, et al. Comparison of placenta samples with contamination controls does not provide evidence for a distinct placenta microbiota. Microbiome. 2016; 4(1):29. doi: 10.1186/s40168-016-0172-3.

de Goffau MC, Lager S, Sovio U, et al. Human placenta has no microbiome but can contain potential pathogens. Nature. 2019; 572(7769):329-34. doi: 10.1038/s41586-019-1451-5.

Dominguez-Bello MG, De Jesus-Laboy KM, Shen N, et al. Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer. Nat Med. 2016; 22(3):250-3. doi: 10.1038/nm.4039.

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When do bacteria first colonize the body? How host-microbe symbiosis is established in early life and its impact on neonatal health - Gut Microbiota...

1st December is World AIDS Day which raises awareness of HIV and AIDS around the world. There have been huge leaps in the treatment of HIV and AIDS in recent years but its still important to raise awareness and support people to live well with HIV.

To mark World AIDS Day 2019 there are a number of initiatives happening around the world. The Terrence Higgins Trust is campaigning to end HIV transmissions in the UK by 2030. The National AIDS Trust is encouraging people to Rock the Ribbon Together and wear their red ribbon to take the isolation out of HIV, show support for people living with HIV and commemorate those who have died from an AIDS-related illness. The World Health Organization and UNAIDS are recognising the essential role of communities in the AIDS response at international, national and local levels.

What are HIV and AIDS?

Human immunodeficiency virus (HIV) affects the bodys immune system and damages the cells. The virus continues to affect the immune system which leads to immunodeficiency. This makes people with HIV more susceptible to infection and disease as the immune system cannot fight them.

Acquired immunodeficiency syndrome (AIDS) is the collection of illnesses, symptoms or infec-tions that can affect the individual when their immune system has been severely affected by HIV. These can be life-threatening.

MSD has been at the forefront of several break throughs in the HIV field

Symptoms and infection

If people are not receiving effective treatment, HIV can be transmitted via some body fluids, including through condomless sex, blood transfusion, contaminated needles, and vertical transmission (from mother to baby during pregnancy or through breastfeeding.)

People may not be aware that they have acquired HIV because they may only experience flu-like symptoms. This is called a seroconversion illness and common symptoms include sore throat, fever and a rash.

According to the Terrence Higgins Trust (THT), seroconversion is a sign that the immune system is reacting to the presence of the virus in the body. Its also the point at which the body produces antibodies to HIV. Once seroconversion has happened, an HIV test will detect antibodies and give a positive result.

Seroconversion illness happens to most (but not all) people shortly after infection. It can be severe enough to put someone in hospital, or so mild that its mistaken for something like flu although a blocked or runny nose is not usually a symptom.

If a person has recently acquired HIV and has not been diagnosed and started treatment, some of their body fluids (eg blood, seminal fluid, vaginal fluid) can be infectious in the early weeks and months after transmission. However, once a person has been diagnosed and is on effective treat-ment, their viral load becomes undetectable, which means they cannot pass on HIV. It can take up to six months from starting treatment to becoming undetectable, but many patients achieve an unde-tectable viral load much sooner than that.

Developments with treatments

There are more than 25 anti-HIV drugs, divided into six classes. Each class works against HIV in a specific way with most people on a fixed dose combination pill. THT classes these as:

Antiretroviral therapy

Antiretroviral therapy (ART) is medication which stops the virus from reproducing in the body. It can reduce the amount of virus in the blood to undetectable levels meaning it cannot be passed on. It is recommended that people start antiretroviral treatment as soon as they are diagnosed with HIV.

PrEP

PrEP, or pre-exposure prophylaxis, is a drug taken by HIV-negative people to reduce the risk of getting HIV. PrEP is a two NRTIs combination drug, which blocks HIV and considerably reduces the risk of transmission. PrEP is taken either on a daily basis or as event-based therapy (on the days before, of, and after condomless sex). However, dosing recommendations will depend upon the type of sex (anal or vaginal). There is currently a PrEP IMPACT Trial taking place in England until the end of 2019, which is recruiting 26,000 participants who are at high risk of HIV. The trial is to assess the need for PrEP in England, not the effectiveness of PrEP, which has already been established in earlier trials.

RIVER study

The RIVER study was a clinical trial designed to wake up and then kill the HIV virus in people in whom it was controlled by antiretroviral treatment, in the hope that by doing so, researchers would be able to cure HIV by completely eradicating the virus from the body. The RIVER study ran from 2015 to 2018 and was led by investigators from Imperial College London, the University of Oxford, MRC Clinical Trials Unit at UCL, and the University of Cambridge.

On publication of initial findings, RIVER Chief Investigator, Professor Sarah Fidler of Imperial College London, said: In the RIVER study, we found that all the separate parts of the kick and kill approach worked as expected and were safebut the study has shown that this particular set of treatments together didnt add up to a potential cure for HIV, based on what weve seen so far.

Remission

There have been two confirmed cases of HIV remission reported. The first case, the Berlin Patient received a stem cell transplant from a donor to treat leukaemia. The donor had two copies of the CCR5 32 allele, a genetic mutation that prevents expression of an HIV receptor CCR5.

In March 2019, news was released that HIV remission had been achieved in a second person. The case, published in Nature and carried out by scientists at University College London, Imperial Col-lege London, the University of Cambridge and the University of Oxford, said a second person had experienced sustained remission from HIV-1 after ceasing treatment. The male patient was diag-nosed with HIV infection in 2003 and had been on antiretroviral therapy since 2012. Later in 2012, he was diagnosed with advanced Hodgkins Lymphoma. In addition to chemotherapy, he under-went a haematopoietic stem cell transplant from a donor with two copies of the CCR5 J32 allele in 2016.

Despite these two cases, researchers say the treatment is not considered appropriate due to the tox-icity of chemotherapy. However, understanding the mechanisms behind these cases may lead to a potential cure in the future.

HIV treatment has progressed significantly in recent years meaning that people living with HIV and receiving appropriate treatment can expect a normal life expectancy

Becoming undetectable

An important breakthrough in HIV research looks at transmission from an HIV positive person to an HIV negative partner. Two studies, PARTNER 1 published in July 2016, and PARTNER 2 published in 2018 and reported in the Lancet in May 2019, both report zero HIV transmissions from a positive partner on ART to their negative partner through sex without using a condom. In PARTNER 1, this was after nearly 900 couples, both heterosexual and gay, had sex more than 58,500 times without using condoms, and in PARTNER 2 almost 800 gay couples had sex more than 77,000 times without using condoms.

Together, these studies contributed to the evidence that led to Undetectable = Untransmittable and support U=U. This means there is zero risk of transmitting HIV when viral load is undetectable.

The 90-90-90 UNAIDS targets call for 90% of those living with HIV to be diagnosed, 90% to be on treatment and 90% of those treated to have an undetectable viral load.

By November 2018, public health data suggested that the UK was doing well against these targets with 92% diagnosed, 98% on treatment and 97% having an undetectable viral load.THTs Cant Pass It On campaign to end HIV transmission altogether and end stigma about the virus, is raising awareness of the facts around HIV and effective treatment, communicating that someone living with HIV and on effective treatment cant pass it on.

MSDs work in HIV

MSD has been at the forefront of several breakthroughs in the HIV field including being the first to publish the crystal structure of HIV protease. New scientific innovation remains crucial but beyond this, MSD continues to stand alongside the global community of people living with HIV. Living well with HIV starts with a person knowing their status and accessing effective treatment, but the needs of the HIV community go well beyond this.

In the UK, MSD continues to partner with the community to tackle stigma and inequalities and help put people at the centre of their own care. The Whole Person Care Partnership is a group of lead-ing HIV organisations which have worked with MSD to establish the importance of sound public policy in these areas.

Anyone whose HIV is undetectable in the blood cannot pass on the virus sexually. This concept is known as Undetectable Equals Untransmittable or U=U. MSD recently collaborated with its Whole Person Care partners in a U=U social media campaign, reaching more than half a million people. The campaign draws links between U=U and stigma, self- management, care planning and inequalities. Such initiatives are just a start and the short films making up the campaign can be found on the MSD-in-the-UK YouTube channel. The aim for everyone involved in the HIV field is to make living well with HIV a reality, one day, for everyone.

The future

HIV treatment has progressed significantly in recent years meaning that people living with HIV and receiving appropriate treatment can expect a normal life expectancy. Work still needs to be done but organisations from the pharmaceutical industry to THT and the World Health Organiza-tion are working hard to change the landscape.

With thanks to British HIV Association and Terrence Higgins Trust

Go to http://www.bhiva.org and http://www.tht.org.uk

Sources:

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Living well with HIV and AIDS around the world - Pharmafield

MB-107 preceded by low-dose busulfan conditioning continues to be well tolerated and results in development of functional immune system in newly diagnosed infants with XSCID

Enhanced transduction procedure is demonstrating improvements in older patients with XSCID who received prior hematopoietic stem cell transplantation

Data presented by St. Jude Childrens Research Hospital and National Institutes of Health at 61st American Society of Hematology Annual Meeting

NEW YORK, Dec. 09, 2019 (GLOBE NEWSWIRE) -- Mustang Bio, Inc. (Mustang) (NASDAQ: MBIO), a clinical-stage biopharmaceutical company focused on translating todays medical breakthroughs in cell and gene therapies into potential cures for hematologic cancers, solid tumors and rare genetic diseases, announced today that updated Phase 1/2 clinical data for MB-107 lentiviral gene therapy for X-linked severe combined immunodeficiency (XSCID) were presented on Saturday by St. Jude Childrens Research Hospital (St. Jude) and today by the National Institutes of Health at the 61st American Society of Hematology (ASH) Annual Meeting.

MB-107 is currently being assessed in two Phase 1/2 clinical trials for XSCID: the first in newly diagnosed infants under the age of two at St. Jude, and the second in patients over the age of two who have received prior hematopoietic stem cell transplantation at the National Institutes of Health. Under a licensing partnership with St. Jude, Mustang intends to develop the lentiviral gene therapy for commercial use as MB-107. The U.S. Food and Drug Administration (FDA) granted Regenerative Medicine Advanced Therapy (RMAT) designation to MB-107 for the treatment of XSCID in August 2019.

Manuel Litchman, M.D., President and Chief Executive Officer of Mustang, said, The updated clinical data presented at the 2019 ASH Annual Meeting underscore the curative potential of MB-107 for newly diagnosed infants with XSCID, as well as its meaningful impact on older XSCID patients who received prior hematopoietic stem cell transplantation. St. Jude recently received the 2019 Smithsonian Magazine American Ingenuity Award for development of the lentiviral gene therapy, highlighting its potential to have an impact on this devastating disease. We are excited to be working with St. Jude and NIH to advance MB-107 and look forward to transferring the IND from St. Jude to Mustang in the first quarter of 2020.

Lentiviral Gene Therapy with Low Dose Busulfan for Infants with X-SCID Results in the Development of a Functional Normal Immune System: Interim Results of an Ongoing Phase I/II Clinical Study (Abstract Number: 2058)Poster presentation: Ewelina Mamcarz, M.D., Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Childrens Research Hospital, Memphis, TN, USA

Interim data from the multicenter Phase 1/2 clinical trial for infants under the age of two treated with the lentiviral gene therapy preceded by low exposure-targeted busulfan conditioning were published in the New England Journal of Medicine. Updated data presented at the 2019 ASH Annual Meeting include three more patients (n=11), 8 months additional median follow up (23.6 months; range: 1.5 to 33.9 months), more extensive analysis of T and B cell functional recovery, and detailed vector integration site studies.

Data Highlights:

The results from treatment with low-dose busulfan conditioning and the novel lentiviral gene therapy in newly diagnosed infants with XSCID continue to be very promising, said Dr. Mamcarz. We are pleased that the therapy has been well tolerated and all patients with a follow up of more than 3 months recovered from pre-existing infections, are off protective isolation and prophylactic antimicrobials, and have normal growth in respect to height and weight. This reinforces our belief that the lentiviral gene therapy has the potential to be an attractive alternative to current XSCID therapies.

Enhanced Transduction Lentivector Gene Therapy for Treatment of Older Patients with X-Linked Severe Combined Immunodeficiency (Abstract Number: 608)Oral presentation: Harry Malech, M.D., Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD, USA

Early outcome data for five older children and young adults with XSCID who received the lentivector (also known as lentiviral) gene therapy as salvage therapy after having previously received haplo-identical hematopoietic stem cell transplantation (HSCT) as infants without chemotherapy-based conditioning were previously reported and published in Science Translational Medicine. By 2016, three additional patients were treated, and the cohort of eight patients (referred to as Cohort A) has now been followed for 3 to 7 years. Among Cohort A, gradual clinical benefit in the clearance of chronic norovirus and associated improved abdominal complaints, malabsorption, growth and IgG production were observed, and four patients were able to cease immunoglobulin replacement therapy.

While the results were positive, the relatively inefficient transduction of hematopoietic stem/progenitor cells (HSPCs) required large quantities of vector. This resulted in relatively low VCN in myeloid cells in some patients, with delayed immune cell recovery and persistent clinical disease, especially in the last patient treated (patient 8). To address this, NIH developed a refined enhanced transduction (ET) procedure consisting of a single overnight transduction after 48 hours pre-stimulation in cytokines (Stem cell factor, Thrombopoietin, Flt3-ligand; 100ng/mL) and incorporated transduction enhancers LentiBoost 1:100 and dimethyl prostaglandin 2 (dmPGE2; 1uM).

The presentation at the 2019 ASH Annual Meeting included data from six patients (referred to as Cohort B) treated by NIH, including re-treatment of patient 8. The patients, who were aged 12 to 36, had significant problems with donor T cell infiltration of liver, bone marrow and kidneys, and were nearly absent of B and NK cells. The enhanced transduction procedure achieved much greater transduction efficiencies than were observed in Cohort A, with greater than 10-fold less vector, and resulted in faster immune reconstitution and more significant clinical benefit by 3 months.

We are encouraged by the significantly improved measures of early clinical outcomes from lentivector gene therapy in older children and young adults with XSCID using an enhanced transduction procedure with the addition of LentiBoost and dmPGE2, said Dr. Malech. Notably, we have seen an early appearance of B and NK cells at much higher levels in Cohort B than we previously observed in Cohort A, even at years after treatment. We look forward to continuing to closely monitor patients and report outcomes.

About Mustang BioMustang Bio, Inc. (Mustang) is a clinical-stage biopharmaceutical company focused on translating todays medical breakthroughs in cell and gene therapies into potential cures for hematologic cancers, solid tumors and rare genetic diseases. Mustang aims to acquire rights to these technologies by licensing or otherwise acquiring an ownership interest, to fund research and development, and to outlicense or bring the technologies to market. Mustang has partnered with top medical institutions to advance the development of CAR T and CRISPR/Cas9-enhanced CAR T therapies across multiple cancers, as well as a lentiviral gene therapy for XSCID. Mustang is registered under the Securities Exchange Act of 1934, as amended, and files periodic reports with the U.S. Securities and Exchange Commission. Mustang was founded by Fortress Biotech, Inc. (NASDAQ: FBIO). For more information, visit http://www.mustangbio.com.

ForwardLooking Statements This press release may contain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934, each as amended. Such statements include, but are not limited to, any statements relating to our growth strategy and product development programs and any other statements that are not historical facts. Forward-looking statements are based on managements current expectations and are subject to risks and uncertainties that could negatively affect our business, operating results, financial condition and stock value. Factors that could cause actual results to differ materially from those currently anticipated include: risks relating to our growth strategy; our ability to obtain, perform under and maintain financing and strategic agreements and relationships; risks relating to the results of research and development activities; risks relating to the timing of starting and completing clinical trials; uncertainties relating to preclinical and clinical testing; our dependence on third-party suppliers; our ability to attract, integrate and retain key personnel; the early stage of products under development; our need for substantial additional funds; government regulation; patent and intellectual property matters; competition; as well as other risks described in our SEC filings. We expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in our expectations or any changes in events, conditions or circumstances on which any such statement is based, except as required by law.

Company Contacts:Jaclyn Jaffe and William BegienMustang Bio, Inc.(781) 652-4500ir@mustangbio.com

Investor Relations Contact:Daniel FerryLifeSci Advisors, LLC(617) 430-7576daniel@lifesciadvisors.com

Media Relations Contact:Tony Plohoros6 Degrees(908) 591-2839tplohoros@6degreespr.com

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Mustang Bio Announces Updated Clinical Data on MB-107 Lentiviral Gene Therapy for Patients with X-Linked Severe Combined Immunodeficiency -...

DetailsCategory: VaccinesPublished on Monday, 09 December 2019 10:31Hits: 95

BASEL, Switzerland I December 9, 2019 I Nouscom, an immuno-oncology company developing off-the-shelf and personalized cancer neoantigen vaccines, announced today that the first patient has been dosed in a Phase 1 clinical trial evaluating its lead candidate, NOUS-209. In this first-in-human trial NOUS-209, an off-the-shelf therapeutic vaccine based on shared tumor neoantigens, is being administered to patients with Microsatellite Instable High (MSI-H) gastric, colorectal and gastro-esophageal junction cancers (tumors characterized by a defective DNA mismatch repair system) in combination with the anti-PD-1 checkpoint inhibitor pembrolizumab.

NOUS-209-01 (NCT04041310) is a US multicenter Phase 1 open-label, dose-escalation study, assessing the safety and tolerability of the NOUS-209 vaccine in combination with pembrolizumab to determine the recommended Phase 2 dose. The study will evaluate vaccine-induced immune responses, as well as preliminary signs of anti-tumor activity in enrolled patients. Based on preclinical data, NOUS-209 is expected to induce potent and broad CD8+ and CD4+ responses in humans. Initial clinical data are expected in 2020.

Dr. Michael J. Overman, Principal Investigator of the trial and Professor in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, explained: "We have seen tremendous change in our approach to MSI-high metastatic solid tumors over the last few years, but the majority of patients do not respond to single agent immunotherapy. Hence, further optimization of our approach for MSI-high cancers is needed. Agents like NOUS-209 that stimulate the patient's immune response and direct it specifically against the cancer cells reflect a tremendous scientific evolution in our understanding of these cancers and represents an extremely promising approach for these cancers."

Dr. Elisa Scarselli, Chief Scientific Officer and Co-Founder of Nouscom, said "This first-in-human trial evaluating NOUS-209 in combination with pembrolizumab is a significant milestone for Nouscom. NOUS-209 leverages a core strength of the company's platform, namely the capacity of its proprietary viral vectors to encode a large number of neoantigens. NOUS-209 was named because it comprises 209 shared Frame Shift Peptides (FSPs) selected using a proprietary algorithm. This feature of NOUS-209 enables it to be developed as an off-the-shelf neoantigen vaccine that does not require patient screening prior to treatment. Furthermore, it is designed to have broad coverage across the MSI patient population by targeting multiple neoantigens in each patient, and as such is expected to address tumor heterogeneity.We look forward to the initial clinical data in 2020."

About Nouscom

Nouscom is a privately held oncology company developing next-generation immunotherapies. Nouscom's proprietary technology platform harnesses the full power of the immune response by combining viral vectored genetic vaccines based on neoantigens with other immunomodulators.

Nouscom is currently advancing the development of its lead program, NOUS-209, an off-the-shelf cancer vaccine based on shared frame shift neoantigens, into clinical studies. The Company will also continue to develop its product candidate, NOUS-PEV, a personalized cancer neoantigen- vaccine, which is expected to enter clinical studies in 2020.

Nouscom is led by an experienced management team that has worked together for many years in previous successful enterprises, including Merck, Novartis, and Okairos (acquired by GSK), and are veterans in the field of viral vectored genetic vaccines.

Nouscom, which was founded in 2015 and is headquartered in Basel, Switzerland with operations in Rome, Italy, is backed by international life sciences investors: 5AM, Abingworth, LSP (Life Sciences Partners) and Versant Ventures.

For more information on Nouscom, please visit the company's website at http://www.nouscom.com.

SOURCE: Nouscom

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Nouscom - First Patient Dosed in a Phase 1 Trial With NOUS-209, an 'off-the-shelf' Neoantigen Cancer Vaccine, in MSI-High Solid Tumors | Vaccines |...

Worldwide more than 140,000 people died from measles in 2018, according to new estimates from the World Health Organization (WHO) and the United States Centers for Diseases Control and Prevention (CDC). These deaths occurred as measles cases surged globally, amidst devastating outbreaks in all regions.

Most deaths were among children under 5 years of age. Babies and very young children are at greatest risk from measles infections, with potential complications including pneumonia and encephalitis (a swelling of the brain), as well as lifelong disability - permanent brain damage, blindness or hearing loss.

Recently published evidence shows that contracting the measles virus can have further long-term health impacts, with the virus damaging the immune systems memory for months or even years following infection. This immune amnesia leaves survivors vulnerable to other potentially deadly diseases, like influenza or severe diarrhoea, by harming the bodys immune defenses.

The fact that any child dies from a vaccine-preventable disease like measles is frankly an outrage and a collective failure to protect the worlds most vulnerable children, said Dr Tedros Adhanom Ghebreysus, Director-General of the World Health Organization. To save lives, we must ensure everyone can benefit from vaccines - which means investing in immunization and quality health care as a right for all.

Measles is preventable through vaccination. However, vaccination rates globally have stagnated for almost a decade. WHO and UNICEF estimate that 86% of children globally received the first dose of measles vaccine through their countrys routine vaccination services in 2018, and fewer than 70% received the second recommended dose.

Worldwide, coverage with measles vaccine is not adequate to prevent outbreaks. WHO recommends that 95% vaccination coverage with two doses of measles vaccine is needed in each country and all communities to protect populations from the disease.

Estimating the total number of cases and deaths globally and by region, the report finds that the worst impacts of measles were in sub-Saharan Africa, where many children have persistently missed out on vaccination.

In 2018, the most affected countries - the countries with the highest incidence rate of the disease - were Democratic Republic of the Congo (DRC), Liberia, Madagascar, Somalia and Ukraine. These five countries accounted for almost half of all measles cases worldwide.

Weve had a safe and effective measles vaccine for over 50 years, said Dr. Robert Linkins, Branch Chief of Accelerated Disease Control and Vaccine Preventable Disease Surveillance at the CDC and Chair of the Measles & Rubella Initiative. These estimates remind us that every child, everywhere needs and deserves - this life-saving vaccine. We must turn this trend around and stop these preventable deaths by improving measles vaccine access and coverage.

While the greatest impacts have been in the poorest countries, some wealthier countries have also been battling measles outbreaks, with significant ramifications for peoples health.

This year, the United States reported its highest number of cases in 25 years, while four countries in Europe - Albania, Czechia, Greece and the United Kingdom lost their measles elimination status in 2018 following protracted outbreaks of the disease. This happens if measles re-enters a country after it has been declared eliminated, and if transmission is sustained continuously in the country for more than a year.

The Measles & Rubella Initiative (M&RI) which includes the American Red Cross, CDC, UNICEF, the United Nations Foundation and WHO as well as Gavi, the Vaccine Alliance, are helping countries respond to measles outbreaks, such as through emergency vaccination campaigns.

In addition to rapidly immunizing against measles, outbreak response also includes efforts to reduce the risk of death through timely treatment, especially for related complications like pneumonia. With partners, WHO is therefore providing support to help countries manage cases, including training health workers in effective care for children suffering the effects of the disease.

Beyond outbreak response, there is an urgent need for countries and the global health community to continue investing in high quality national immunization programmes and disease surveillance, which helps ensure measles outbreaks are rapidly detected and stopped before lives are lost.

It is a tragedy that the world is seeing a rapid increase in cases and deaths from a disease that is easily preventable with a vaccine, said Dr Seth Berkley, CEO of Gavi, the Vaccine Alliance. While hesitancy and complacency are challenges to overcome, the largest measles outbreaks have hit countries with weak routine immunization and health systems. We must do better at reaching the most vulnerable, and that will be a fundamental focus of Gavis next five-year period.

Over the last 18 years, measles vaccination alone is estimated to have saved more than 23 million lives.

M&RI is a global partnership founded by the American Red Cross, the CDC, the United Nations Foundation, UNICEF and WHO, that is committed to achieving and maintaining a world without measles, rubella and congenital rubella syndrome. Founded in 2001, the Initiative has helped vaccinate over 2.9 billion children and save over 21 million lives by increasing vaccination coverage, improving disease response, monitoring and evaluation, and building public confidence and demand for immunization.

We are alarmed at the increase in measles in the US and around the globebut there is hope, said Gail McGovern, President & CEO, American Red Cross. Measles outbreaks are entirely preventable through strong systems that ensure no child misses lifesaving vaccines.

The unacceptable number of children killed last year by a wholly preventable disease is proof that measles anywhere is a threat to children everywhere, said Henrietta Fore, UNICEFs Executive Director. When children go unvaccinated in significant numbers, entire communities are at risk. We see that eventoday in remote places like in the Democratic Republic of the Congo,where measles has killed more than 4,500 children under the age of five so far this year; or in Samoa, where a rapidly spreading measles outbreak has left many children ill and unable to go to school.

This latest data show that we are unfortunately backsliding in our progress against an easily-preventable disease: measles, said Kathy Calvin, President and CEO of the United Nations Foundation. But we can turn the tide against these outbreaks through collective action, robust political commitment, and closing critical funding gaps. Working together worksits the only way we will be able to reach everyone, everywhere with life-saving vaccines and services and, more broadly, reach the UNs Sustainable Development Goals.

Progress Toward Regional Measles Elimination Worldwide, 20002017 is a joint publication of WHO and CDC. It is published within the WHO Weekly Epidemiological Record and in CDCs Morbidity and Mortality Weekly Report.

Measles elimination is defined as the absence of endemic measles virus transmission in a region or other defined geographical area for more than 12 months. Conversely, a country is no longer considered to be measles free if the virus returns and transmission is sustained continuously for more than a year.

These estimates are the result of statistical modeling undertaken by WHO. Each year, the model is adjusted for the entire time series from 2000 to the current year. This years modelling shows that there were 9,769,400 estimated measles cases and 142,300 related deaths globally in 2018, decreasing from 28,219,100 cases and 535,600 deaths in 2000. In 2017, there were 7,585,900 estimated cases and 124,000 estimated deaths.

By region in 2018, WHO estimates that in the African region, there were 1,759,000 total cases and 52,600 deaths; in the Region of the Americas, 83,500 cases; in the Eastern Mediterranean Region, 2,852,700 cases and 49,000 deaths; in the European region, 861,800 cases and 200 deaths; in Southeast Asia, 3,803,800 cases and 39,100 deaths; and in the Western Pacific, 408,400 cases and 1300 deaths.

While estimates provide a useful indication of measles impacts and longer-term trends, reported cases provide real-time insights and comparisons. There were a total of 353,236 cases reported to WHO in 2018. In 2019, as of mid-November, there had already been over 413,000 cases reported globally, with an additional 250,000 cases in DRC (as reported through their national system); together, this marks a three-fold increase compared with this same time in 2018.

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More than 140,000 die from measles as cases surge worldwide - World Health Organization

Chimeric antigen receptor (CAR) T-cell therapy targeting both BCMA and CD38 induced promising responses among patients with multiple myeloma who had been treated with at least 3 prior therapies and whose disease had spread outside of the bone marrow, supporting further exploration of the dual-targeted therapy, according to Yu Hu, MD, PhD.

This is the first clinical trial of anti-BCMA and CD38 dual-targeted CAR T-cell therapy in refractory multiple myeloma. Our study demonstrates improved efficacy and manageable safety, Hu, of Union Hospital at Huazhong University of Science and Technology in Wuhan, China, said during a presentation to an audience at the 61st Annual American Society of Hematology Annual Meeting and Exposition.

The objective response rate was 90.1%, with 12 patients achieving a stringent complete response (sCR) as their best response, meaning that no plasma cells were detected in the bone marrow. Seven patients (31.8%) had a partial response (PR), meaning that the level of M-protein in the blood or urine was reduced but still detectable, with 2 achieving a very good partial response (VGPR). One patient had a minor response. Eighteen patients (81.8%) reached bone marrow minimal residual diseasenegative status.

At the cutoff date of October 31, 2019, 19 patients were still alive with 10 still in sCR, 1 with VGPR, 4 with PRs. Three patients experienced relapse and 1 patient had progressive disease.

The median progression-free survival (PFS) had not been reached with a PFS rate at 9 months of 78.9%. For 17 patients remaining in remission at 7 months after treatment, median duration of response was 28.8 weeks.

Cytokine release syndrome (CRS) was observed in 20 out of 22 patients (90.9%), with 11 having grade 1 CRS and 4 with grade 2. Severe CRS grade 3 occurred in 5 (22.7%) and only 6 patients overall required treatment. No neurotoxicity was observed. Hepatotoxicity was seen in 3 patients (13.6%) and 1 patient experienced nephrotoxicity.

The peak time of CAR T cells in peripheral blood occurred from day 7 to day 15 after infusions in patients who achieved sCR and from day 14 to day 30 in patients without sCR. The longest duration of CAR T cells in the peripheral blood was >450 days. BM38 CAR was tested by quantitative polymerase chain reaction (qPCR) in the peripheral blood.

Eight out of 9 patients achieved complete or partial response of extramedullary disease, meaning these tumors were undetectable by CT scan.

With this dual-targeted CAR T-cell therapy, we have demonstrated a high response rate, especially a higher rate and longer duration of stringent complete response, compared with other therapies, as well as effective elimination of extramedullary lesions, with no serious neurologic adverse effects and manageable levels of other adverse effects, Hu said.

Among patients with multiple myeloma, roughly 10% will develop tumors in their organs or soft tissue known as extramedullary tumors. Patients who develop these often have poor responses to available therapies, experience a decrease in their quality of life, and have poor prognoses. According to Hu, patients treated in the study demonstrated that the novel dual-targeting CAR T-cell therapy may effectively eliminate extramedullary tumors.

This new CAR T cell [therapy] may have effects on the suppressor B cell. That means you can overcome the immunosuppression of the tumor environment, Hu said.

In total, 22 patients with a median age of 59 year (range, 49-72), half of whom were male, were treated in the dose-climbing phase I trial. All patients had multiple myeloma that had returned or not responded to at least 3 prior therapies. Nine patients (41%) had extramedullary tumors. Myeloma cells in the bone marrow were observed at a median of 9.7% (0.50%-56.1%) by flow cytometry. Seventy-three percent of patients had cytogenetic abnormalities such as 1q21 amp (54.6%) and deletion of chromosome 13q (40.9%).

All patients were treated with a 3-day chemotherapy regimen of fludarabine at 25 mg/m2 and cyclophosphamide 250 mg/m2 to make room in the immune system for engineered CAR T cells before infusion with the product. Patients were infused with CAR T cells at 0.5 106/kg to 4.0 106/kg with at least 2 patients treated at every dose level.

Investigators plan to continue follow up on these patients for 2 years. A phase II trial is being planned in both China and the United States to test the treatments efficacy in a larger number of patients.

Reference:

Mei H, Hu Y, Li C, et al. A bispecific CAR-T cell therapy targeting BCMA and CD38 for relapsed/refractory multiple myeloma: updated results from a phase 1 dose-climbing trial. Presented at: 61st Annual American Society of Hematology Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL. Abstract 930. https://bit.ly/38imXXG.

This article originally appeared on OncLive, titled Extramedullary Multiple Myeloma Responds to Dual-Targeting CAR T-Cell Therapy.

Link:
Promising Responses from Dual-Targeting CAR T-Cell Therapy in Myeloma Support Further Exploration - Cancer Network

There's more to this trusty festive staple thank you might think, writes Fiann Nuallin.

The only time some people partake of Brussels sprouts is in a festive scenario. Well there is much more to sprouts (Brassica oleracea, from Gemmifera group of cabbages) than the tradition of dressing the plate beside the stuffing.

Packed with antioxidants and dietary fibre they serve to mop up a lot of the junk we indulge in at this time of the year but also are worth becoming a regular in the five-a-day rota during the rest of the year.

I say the rest of the year as they freeze beautifully but in terms of fresh seasonality they are in the main, a winter crop with a season than starts in October and ends in March. Garden-grown varieties can be set up to begin producing from mid-August.

There are early and late cultivars but generally the tradition is, for early harvests to sow under cover or in a cold frame in February or March. Otherwise sow or plant plugs from late April/early May.

Pick a sheltered, sunny site, to grow on.

The sprouts are little fibre bullets supporting intestinal health and helping to lower blood sugars and high lipid accumulations from triglycerides to cholesterol. Dietary fibre is of prime importance to anyone dealing with diabetes, high cholesterol and digestive conditions.

The fibre and the stomach-strengthening phytochemistry of sprouts have seen them included in dietsto support Crohns disease, irritable bowel syndrome, and ulcerative colitis.

Brussels sprouts contain an antibacterial agent known as glucoraphanin which protectsthe stomach from bacterial overgrowth particularly good in fighting off candida and Helicobacter pylori.

They are often though of as a detox or system cleanse vegetable.

The richness of their glucosinolates have been studied as valid triggers to the detoxification and clearance of cancer-causing substances. Those sulphur-rich molecules also drive a better immune system.

The boost to the whole system is derived from the amazing quality of Brussels sprouts antioxidants.

Packed with vitamin C and beta-carotene to mop up free radical damage and protect our DNA and cellular health but also filled with fabulous flavonoid such as caffeic acid, ferulic acid, isorhamnetin, quercitin, and kaempferol all not just limiting the ageing process but working to disarm allergies and inflammation.

Brusssels sprouts are one of the bestanti-inflammatory vegetables, in part due to the high vitamin K content which regulates inflammatory responses but also via thede-inflaming action of glucosinolates one in particular glucobrassicin has shown effective in limiting rheumatoid arthritis flare-ups.

The glucobrassicin molecule converts into isothiocyanate which may be helpful in improving insulin resistance by lessening inflammation that complicates diabetes.

Sprouts contain zea-xanthin known as an eye health carotenoid beneficial to prevent age-related macular degeneration and bolster eyesight in general, those 20/20 rabbits eat more than carrots.

Sprouts also supply omega-3 fatty acids, and one of them is alpha-linolenic acid which is of benefit to the cardiovascular system and support the nervous system.

Ala is also known to lower inflammation, blood pressure and cholesterol levels.

When it comes to diets for cancer prevention and recovery, glucosinolates in cruciferous vegetables often hit the headlines. Of all the crucifers, Brussels sprouts contain the most and easily activated levels of sulforaphanes and isothiocyanates known to offer protection from colonic, prostate and endometrial cancers.

These same agents are helpful in battling viral and bacterial infections that can affect us across winter months. The trick is to leave enough sprout phytochemistry intact to do the job most effectively and thats down to how you cook.

In recent years, perhaps as a drive to boost flagging sales, the odd celebrity chef appears with a roasted sprout and chestnut dish or a roasted honey-glazed sprout.

Great and tasty but to get the best from sprouts, steam them. Years of boiling to a sulphurous sog has put many off. If you smell the cabbage aroma you have overcooked the sprout. Steaming is fast and less aromatic.

Steaming also keeps those healthy phytochemicals more integral and ready to be absorbed upon eating.

A 4-6-minute steam will do the trick. As some of the sprouts chemistry is enzymatically released, it is a good idea to slice in half or quarter and allow the chopped parts to sit for five minutes before cooking. This action lets the enzymes at the cuts do their thing.

Abacus is an easy-to-grow early tomid-season cropper. Good solid sprouts.

Bosworth is an easy-to-grow late cropper best yields after Christmas into spring.

Brigitte F1 is a favourite among Irish growers quite nutty in flavour but also a long season and disease resistance.

Crispus F1 is a mid-season, clubroot-resistant variety. Small, tight sprouts.

Chronos is a clubroot-resistant variety, grown as a mid-season.

Diablo is a mid-to-late-season cropper. Dark green sprouts.

Evesham Special is a shorter growing but long and prolific harvester from September on.

Maximus is one of the early to mid-season croppers. Plenty of mid- to dark- green sprouts.

Red Bull Also known as red ball, it yields attractive and tasty dark red sprouts.

Revenge is known as a late variety and can still be vigorous and prolific in spring.

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Why sprouts earn a place on your plate all year round - Irish Examiner