Antibody fights pediatric brain tumors in preclinical testing | News … – Stanford Medical Center Report

The most exciting aspect of our findings is that no matter what kind of brain tumor we tested it against, this treatment worked really well in the animal models, said Cheshier, who is also a pediatric neurosurgeon at Lucile Packard Childrens Hospital Stanford. In mice that had been implanted with both normal human brain cells and human brain cancer cells, there was no toxicity to normal human cells but very, very active tumor-killing in vivo, he said.

Given the encouraging results of the new study and the ongoing research on anti-CD47 antibodies in adults, the antibodies are expected to reach clinical trials in children with brain cancer in one to two years, he added.

The anti-CD47 antibodies help the immune system to detect an important difference between cancerous and healthy cells: Cancer cells make eat me signals that are displayed on their cell surfaces, while healthy cells do not. However, cancer cells hide these eat me signals by producing large quantities of CD47, a dont eat me protein that is found on the surface of both healthy and malignant cells. When CD47 is blocked by antibodies, immune cells called macrophages can detect the cancer cells eat me signals. Macrophages then selectively target, engulf and destroy the cancer cells without harming healthy cells, because normal cells lack the eat me signals.

The Stanford team conducted a long series of experiments using different combinations of tumor cells and healthy cells in culture, as well as in various mouse models in which human brain cancer cells had been implanted in mice. Highlights of their experiments included the following:

The anti-CD47 antibodies did not completely eliminate all tumors, suggesting that the antibodies may not be able to completely penetrate large tumors, the researchers noted.

To maximize their effects, the antibodies will likely need to be combined with other forms of cancer treatment, a concept the researchers plan to investigate further, Cheshier said. In the future, patients may receive combinations of immune therapies and lower doses of standard cancer treatments, he said, adding, The question is: Can we wisely combine immune therapies and other approaches to make cancer treatment more efficacious and less toxic?

Anti-CD47 antibodies also may have an advantage over other immunotherapies in that they activate macrophages, which completely engulf and eat cancer cells, Cheshier noted. In many forms of immunotherapy, the cells you target die and spill their contents, which can cause dysregulated immune responses, he said. Anti-CD47 antibodies may produce fewer such side effects, though the idea remains to be tested.

Other Stanford co-authors of the paper are medical students Abdullah Feroze, Rogelio Esparza and Michael Zhang; postdoctoral scholars Suzana Kahn, PhD, Anne Volkmer, MD and Stephen Willingham, PhD; research assistants Anitha Ponnuswami, Theresa Storm, Cyndhavi Narayanan and Pauline Chu; senior research associate Jie Liu, MD, PhD; undergraduate research associate Chase Richard; Aaron McCarthy, a former life sciences research professional and animal colony manager; Patricia Lovelace, research and development engineer; Simone Schubert, life science researcher; visiting scholar Gregor Hutter, MD, PhD; Griffith Harsh, MD, professor of neurosurgery; Michelle Monje, MD, PhD, assistant professor of neurology; Yoon-Jae Cho, MD, a former assistant professor of neurology and neurological sciences; Ravi Majeti, MD, PhD, associate professor of medicine; senior scientist Jens Volkmer, MD; Paul Fisher, MD, professor of pediatrics; Gerald Grant, MD, associate professor of neurosurgery; Gary Steinberg, MD, PhD, professor of neurosurgery; Hannes Vogel, MD, professor of pathology and of pediatrics; and Michael Edwards, MD, professor of neurosurgery.

Cheshier, Monje, Majeti, Fisher, Grant and Edwards are members of Stanfords Child Health Research Institute. Cheshier, Weissman, Harsh, Monje, Majeti, Fisher, Grant, Vogel and Edwards are members of the Stanford Cancer Institute. Weissman is the director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine and of the Ludwig Center for Cancer Stem Cell Research and Medicineat Stanford.

Scientists from SickKids, the Hospital for Sick Children in Toronto; University Hospital, Dusseldorf; and Johns Hopkins University also contributed to the study.

The study was funded by National Institute of Neurological Disorders and Stroke (grant NINDSK08NS070926); the National Cancer Institute (grant P30CA006973); the California Institute for Regenerative Medicine; the Price Family Charitable Fund; the Center for Childrens Brain Tumors at Stanford; St. Baldricks Foundation; the American Brain Tumor Foundation; the Seibel Stem Cell Institute; the Pew Charitable Trusts; the Dr. Mildred-Scheel Foundation/German Cancer Aid; the German Research Foundation; the McKenna Claire Foundation; the Matthew Larson Foundation; Alexs Lemonade Stand Foundation; The Cure Starts Now; the Lyla Nsouli Foundation; the Dylan Jewett, Connor Johnson, Zoey Ganesh, Dylan Frick, Abigail Jensen, Wayland Villars and Jennifer Kranz memorial funds; the Virginia and D. K. Ludwig Fund for Cancer Research; the Lucile Packard Foundation for Childrens Health; the National Institutes of Health (grant UL1TR001085); the Tashia and John Morgridge Endowed Pediatric Faculty Scholar and Fellowships Awards; and the Anne T. and Robert M. Bass Endowed Faculty Scholarship in Pediatric Cancer and Blood Diseases. The study was also funded by gifts from George Landegger; Rider and Victoria McDowell; Charles Comey and Judith Huang; and Colin and Jenna Fisher.

Stanfords Department of Neurology & Neurological Sciences also supported the work.

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Antibody fights pediatric brain tumors in preclinical testing | News ... - Stanford Medical Center Report

MS: Treatments to reverse myelin damage step closer with brain repair study – Medical News Today

A breakthrough study looking at how the brain repairs itself could revolutionize treatments for multiple sclerosis. The research, performed on mice and tissue cultures, reveals for the first time that a type of cell involved in immune control also releases a protein that triggers regrowth of myelin.

The international study - led by Queen's University Belfast in Northern Ireland, United Kingdom - is published in the journal Nature Neuroscience.

Senior author Dr. Denise Fitzgerald - of the University's Wellcome-Wolfson Institute for Experimental Medicine - describes the findings as "an important step forward in understanding how the brain and spinal cord is naturally repaired."

Worldwide, more than 2.3 million people are affected by multiple sclerosis (MS) - a disease in which the immune system mistakenly attacks the tissue of the central nervous system, which consists of the brain, spinal cord, and optic nerves.

In MS, the immune system attacks and destroys myelin - the fatty, protective sheath that surrounds and insulates nerve fibers.

As the myelin damage increases, it disrupts the signals that travel to and from the brain along the affected nerve fibers. This results in a range of symptoms that include impaired mobility, extreme fatigue, vision problems, pain, and altered sensation.

Although anyone can develop MS, it is the most common neurological disease in young adults and it affects two to three times more women than men.

Fast facts about MS

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There is no evidence that MS is hereditary, but it is thought that genes play a role, as well as certain environmental factors such as low vitamin D and smoking tobacco.

There is currently no cure for MS, although some approved drugs appear to reduce frequency of relapses and delay disease progression to some extent.

The researchers are excited about their discovery because it takes treatment research into the area of reversing myelin damage.

Dr. Fitzgerald has a personal as well as a professional interest in MS - when she was 21, she had to learn to walk again after experiencing a similar condition called transverse myelitis.

The study concerns a type of immune cell called T cells, which, in cases of MS, are known to cross over from the bloodstream into the central nervous system.

Dr. Fitzgerald and colleagues discovered that a subtype of T cells called regulatory T cells - which are already known to be involved in regulating the immune system - also have a role in promoting myelin regrowth.

The regulatory T cells promote myelin regrowth through their effect on oligodendrocytes - the cells that make myelin. The process of myelin regrowth requires oligodendrocyte progenitor cells to mature into oligodendrocyte cells.

The researchers found that regulatory T cells release a protein that stimulates the differentiation of the progenitor cells into mature oligodendrocytes.

They showed that mice deficient in regulatory T cells showed substantially impaired myelin regeneration, which was restored when they transferred regulatory T cells into the mice.

Using cultured brain tissue, the researchers also showed that regulatory T cells "accelerated developmental myelination and remyelination, even in the absence of overt inflammation."

They conclude that their findings reveal a regenerative function for regulatory T cells that is separate from their role in regulating the immune response.

"This exciting study gives us an important understanding of how myelin repair can be promoted, which could open up new areas for treatment development."

Dr. Sorrel Bickley, Head of Biomedical Research at the UK MS Society

Learn how modified red blood cells could lead to new treatments for MS.

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MS: Treatments to reverse myelin damage step closer with brain repair study - Medical News Today

Progress in treating hearing loss – Harvard Gazette

Inside a bony structure that spirals like a snail shell in a humans inner ear, roughly 15,000 hair cells receive, translate, and then ship sound signals to the brain. Damage to these cells from excessive noise, chronic infections, antibiotics, certain drugs, or the simple passing of time can lead to irreparable hearing loss.

Harvard Stem Cell Institute (HSCI) researchers at Brigham and Womens Hospital (BWH) and Massachusetts Eye and Ear Infirmary and colleagues from Massachusetts Institute of Technology (MIT) have developed an approach to replace damaged sound-sensing hair cells, which eventually may lead to therapies for people who live with disabling hearing loss.

In a recent Cell Reports study, the researchers identified a small molecule cocktail that increased the population of cells responsible for generating hair cells in the inner ear. Unlike hair on the human head, the hair cells lining that bony structure, called the cochlea, do not regenerate.

HSCI principal faculty Jeff Karp, HSCI affiliate faculty Albert Edge, and MITs Robert Langer were co-corresponding authors of the study. Will McLean, a postdoctoral fellow in the Edge lab, and Xiaolei Yin, an instructor in medicine at BWH, were co-first authors.

In 2012, Edge and colleagues identified a population of stem cells, characterized by an Lgr5+ marker, which scientists could turn into hair cells in a dish. A year later, Edge had converted the resident population of these cells in mice into hair cells, though the ability to restore hearing using this approach has been limited.

The problem is the cochlea is so small and there are so few cells that it creates a bottleneck limiting the number and types of experiments researchers could perform, said Edge, director of the Tillotson Cell Biology Unit at Mass. Eye and Ear and a professor of otolaryngology at Harvard Medical School (HMS).

However, by exposing Lgr5+ cells isolated from the cochlea of mice to the small molecule cocktail, the researchers were able to create a 2,000-fold increase in the number of stem cells.

Those molecules were a key to unlocking this regenerative capability, said Karp, who is also a bioengineer at BWH and an associate professor of medicine at HMS.

Inspired by creatures with significant regenerative potential, including lizards and sharks, Karps lab initially turned to one of the bodys most highly regenerative tissues, the gastrointestinal lining, which completely replaces itself every four to five days. Central to this process is the paneth cell, neighbor to the intestinal stem cells that are responsible for generating all mature cell types in the intestine. The paneth cells effectively tell the stem cells, also characterized by their Lgr5+ markers, when to turn on and off.

Karp and his colleagues at MIT looked at the basic biology of the ties between paneth cells and intestinal stem cells and identified small molecules that could communicate directly with and control the Lgr5+ stem cells.

While we were developing the approach for the intestinal cells, we demonstrated it also worked in several other tissues with the Lgr5+ stem cells and progenitors, including the inner ear, Karp said.

When the researchers coupled the cocktail with established differentiation protocols, they were able to generate large quantities of functional hair cells in a petri dish. Using protocols from the Edge lab, the researchers then thoroughly characterized the differentiated cells to demonstrate they were functional hair cells. Researchers tested the cocktail on newborn mice, adult mice, non-human primates, and cells from a human cochlea.

We can now use these cells for drug screening as well as genetic analysis, Edge said. Our lab is using the cells to better understand the pathways for expansion and differentiation of the cells.

Additionally, the small molecule cocktail may also be turned into a therapeutic treatment. Karp has co-founded Frequency Therapeutics, which plans to use insights from these studies to develop treatments for hearing loss. The team hopes to begin human clinical testing within 18 months.

Not only is it a potential therapeutic that could be relevant for the restoration of hearing, but this approach is a platform, said Karp. The concept of targeting stem cells and progenitor cells in the body with small molecules to promote tissue regeneration can be applied to many tissues and organ systems.

By Alvin Powell, Harvard Staff Writer | March 15, 2017

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Progress in treating hearing loss - Harvard Gazette

Cutting-edge stem cell therapy proves safe, but will it ever be effective? – Science Magazine

Masayo Takahashi (second from left) treated macular degeneration with retinal tissue grown from iPS cells.

Kyodo News/Contributor/getty images

By Dennis NormileMar. 15, 2017 , 5:00 PM

Its official: The first use of induced pluripotent stem (iPS) cells in a human has proved safe, if not clearly effective. Japanese researchers reported in this weeks issue of The New England Journal of Medicine (NEJM) that using the cells to replace eye tissue damaged by age-related macular degeneration (AMD) did not improve a patients vision, but did halt disease progression. They had described the outcome at conferences, but publication of the details is an encouraging milestone for other groups gearing up to treat diseased or damaged organs with the versatile replacement cells, which are derived from mature tissues.

This initial success is pretty momentous, says Alan Trounson, a stem cell scientist at the Hudson Institute of Medical Research in Melbourne, Australia. But the broader picture for iPS therapies is mixed, as researchers have retreated from their initial hopes of creating custommade stem cells from each patients tissue. That strategy might have ensured that recipients immune systems would accept the new cells. But it proved too slow and expensive, says Shinya Yamanaka of Kyoto University in Japan, who first discovered how to create iPS cells and is a co-author of the NEJM paper. He and others are now developing banks of premade donor cells. Using stocks of cells, we can proceed much more quickly and cost effectively, he says.

Even so, clinical work is progressing more quickly than I had expected, says Yamanaka, who did his groundbreaking work just a decade ago. His collaborator on this trial, Masayo Takahashi of the RIKEN Center for Developmental Biology in Kobe, Japan, had a head start. An ophthalmologist, Takahashi was familiar with the ravages of AMD, a condition that progressively damages the macula, the central part of the retina, and is the leading cause of blindness in the elderly.

Takahashi started investigating treatments for AMD in 2000, a time when the only cells capable of developing into all the tissues of the body had to be extracted from embryos. But she was stymied by immune reactions to these embryonic stem (ES) cells. When Yamanaka announced that he could induce mature, or somatic cells, to return to an ES celllike state, Takahashi quickly changed course to develop a treatment based on iPS cells.

Her team finally operated on the first patient, a 77-year-old Japanese woman with late-stage AMD, in September 2014. They took a sample of her own skin cells, derived iPS cells, and differentiated them into the kind of retinal cells destroyed by the disease. A surgeon then slipped a small sheet of the cells into the retina of her right eye.

An operation on a second patient was called off because a number of minor genetic mutations had crept into his iPS cells during processing, and uncontrolled growthcancerhas been a worry with such cells. These changes do not directly induce cancer, but we wanted to make safety the first priority, Yamanaka says. Also, Takahashi says, AMD drugs had stabilized the patients condition so there was no urgency in subjecting him to the risks of surgery, which include hemorrhaging and retinal damage.

Immediately after surgery the first patient reported her eyesight was brighter. Takahashi says the surgery halted further deterioration of her eye, even without the drug injections still being used to treat her other eye, and there were no signs of rejection of the graft as of last December.

Clinical work is progressing much more quickly than I expected.

The result is a proof of principle that iPS cellbased therapy is feasible, says Kapil Bharti, a molecular cell biologist at the U.S. National Institutes of Healths National Eye Institute in Bethesda, Maryland, who is also developing iPS cells for treating AMD. Takahashi says once her team gains more experience with the technique they will extend it to patients with earlier-stage AMD in an effort to preserve vision.

Last month, Takahashi won approval to try the procedure on another five patients with late-stage AMD. But this time, instead of using iPS cells derived from each patient, the team will draw on banked cells from a single donor. It takes time to create iPS cells, and a lot of time for the safety evaluation, Yamanaka says. It is also costly, at nearly $900,000 to develop and test the iPS cells for the first trial, Takahashi adds.

Using donor cells to create the iPS cells will make it more difficult to ensure immune compatibility. But Yamanaka says that donor iPS cells can be matched to patients based on human leukocyte antigen (HLA) haplotypessets of cell-surface proteins that regulate immune reactions. HLA-matched cells should require only small doses of immunosuppressive drugs to prevent rejection, Takahashi saysand perhaps none at all for transplantation into the immune-privileged eye.

Kyoto Universitys Center for iPS Cell Research and Application, which Yamanaka heads, has been developing an iPS cell bank. Just 75 iPS cell lines will cover 80% of the Japanese population through HLA matching, he says. Trounson, a past president of the California Institute for Regenerative Medicine, a stem cell funding agency, says banked iPS cells have advantages. Donor iPS cells may be safer than cells derived from older patients, whose somatic cells may harbor mutations. And Jordan Lancaster, a physiologist at the University of Arizona in Tucson, likes the speed of the approach. He is devising patches for heart failure patients based on iPS-derived myocardial cells that will be premanufactured, cryopreserved, and ready to use at a moments notice.

Patient-specific iPS cells will still have clinical uses. For one thing, Bharti says it will be difficult for cell banks to cover all HLA haplotypes. And a patients own iPS cells could be used to screen for adverse drug reactions, says Min-Han Tan, an oncologist at Singapores Institute of Bioengineering and Nanotechnology, who recently published a report on the approach.

Other human trials are not far behind. Yamanaka says his Kyoto University colleague Jun Takahashi (Masayo Takahashis husband) will launch trials of iPS-derived cells to treat Parkinsons disease within 2 years. Bharti hopes to start human trials of iPS cells for a different type of macular degeneration next year. And as techniques for making and growing iPS cells improve, researchers can contemplate treatments requiring not just 100,000 cells or sothe number in Takahashis retinal sheetsbut millions, as in Lancasters heart patches.

As clinical use approaches, Takahashi cautions that researchers need to keep public expectations realistic. For now, iPS treatments may help but wont fully reverse disease, she says. Regenerative medicine is not going to cure patients in the way they hope.

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Mesoblast’s (MESO) Regenerative Cell Therapy Proves Itself in Back Pain Trial – Economic Calendar

This morning, Australian biotech company Mesoblast Ltd (NASDAQ:MESO) announced encouraging phase 2 trial data regarding its regenerative therapy for chronic lower back pain (CLBP). Mesoblasts proprietary allogeneic Mesenchymal Precursor Cells (MPCs) are given to patients via a single injection and, in the clinical trial, have proved to spark significant improvement in both lower back pain and function that lasted for at least 36 months.

The sustained benefits on pain and function over three years seen with a single injection of Mesoblasts cell therapy have the potential to transform the treatment paradigm for chronic low back pain due to disc degeneration, said Dr. Hyun Bae, the trial investigator and Director of the Spine Institute.

According to Bae, there is growing evidence that disc degeneration can be healed instead of needing to be replaced or fused. Researchers are quickly arriving at this inflection point in the treatment of lower back pain, which is especially critical given the ongoing opioid abuse epidemic sweeping the nation.

Researchers believe that MPCs are turned on by signals in damaged tissues that spark factors to block damaging inflammation and begin repairing the afflicted area.

The phase 2 trial in question involved 100 patients, who were treated with either six million or 18 million MPCs via one intra-discal injection or a placebo of either saline or hyaluronic aid. The primary endpoints were a 50 percent drop in Visual Analog Scale (CAS), which is a pain metric, and a 15-point reduction in Oswestry disability index (ODI) at both the one and two year marks.

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The primary endpoint composite at the two-year mark was met by 41 percent of patients in the 6 million MPC arm, 35 percent in the 18 million arm, with just 18 percent and 13 percent in the placebo groups. The phase 2 results support the companys criteria for its ongoing phase 3 program.

Mesoblast is confident that the durable treatment outcomes in lower back pain are part of an overarching mechanism that might also have a positive effect in other types of chronic conditions where a single injection of MPCs can lead to sustained benefits. Two of these potential indications, according to Mesoblast, are chronic heart failure and biological-resistant rheumatoid arthritis.

Following the trial data being released, Maxim Groups Jason Kolbert reaffirmed a Buy rating on Mesoblasts stock and maintained a price target at $14.00. The upside indicated is 81 percent.

The market opportunity is significant and the treatment fits ideally within the existing paradigm the analyst told investors this morning. Injecting cells versus steroids with a better AE profile and now a better long-term result.

Earlier this month, Mesoblast announced that its MSC-100-IV therapy had been given Fast Track designation by the Food and Drug Administration (FDA) for its use in children with steroid refractory acute Graft Versus Host Disease (aGVHD). This type of designation shortens the FDA review path from ten months to six months, and certain portions of the Biologics License Application (BLA) can be sent in on a rolling basis rather than when everything is finished.

The author of this article holds no position in any of the stocks mentioned above.

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Mesoblast's (MESO) Regenerative Cell Therapy Proves Itself in Back Pain Trial - Economic Calendar