Healing wounds with cell therapy – Medical Xpress

May 29, 2017

Diabetic patients frequently have lesions on their feet that are very difficult to heal due to poor blood circulation. In cases of serious non-healing infections, a decision to amputate could be made. A new therapeutic approach, presented recently in the Journal of Investigative Dermatology by Canadian researchers affiliated with the University of Montreal Hospital Research Centre (CRCHUM), could prevent these complications by promoting wound healing.

The solution isn't what you might expect, not just another antibiotic ointment or other prescription medication. It's the approach that's different, a way to heal through personalized medicine. "We discovered a way to modify specific white blood cells - the macrophages - and make them capable of accelerating cutaneous healing," explained nephrologist Jean-Franois Cailhier, a CRCHUM researcher and professor at the University of Montreal.

It has long been known that macrophages play a key role in the normal wound healing process. These white cells specialize in major cellular clean-up processes and are essential for tissue repair; they accelerate healing while maintaining a balance between inflammatory and anti-inflammatory reactions (pro-reparation).

"When a wound doesn't heal, it might be secondary to enhanced inflammation and not enough anti-inflammatory activity," explained Cailhier. "We discovered that macrophage behaviour can be controlled so as to tip the balance toward cell repair by means of a special protein called Milk Fat Globule Epidermal Growth Factor-8, or MFG-E8."

Cailhier's team first showed that when there is a skin lesion, MFG-E8 calls for an anti-inflammatory and pro-reparatory reaction in the macrophages. Without this protein, the lesions heal much more slowly. Then the researchers developed a treatment by adoptive cell transfer in order to amplify the healing process.

Adoptive cell transfer consists in treating the patient using his or her own cells, which are harvested, treated, then re-injected in order to exert their action on an organ. This immunotherapeutic strategy is usually used to treat various types of cancer. This is the first time it has been shown to also be useful in reprogramming cells to facilitate healing of the skin.

"We used stem cells derived from murine bone marrow to obtain macrophages, which we treated ex vivo with the MFG-E8 protein before re-injecting them into the mice, and we quickly noticed an acceleration of healing," said Dr. Patrick Laplante, Cailhier's research assistant and first author of the study.

Added Dr. Cailhier, "the MFG-E8 protein, by acting directly upon macrophages, can generate cells that will orchestrate accelerated cutaneous healing."

The beauty of this therapy is that the patient (in this case the mouse) is not exposed to the protein itself. Indeed, as Dr. Cailhier explained, "if we were to inject the MFG-E8 protein directly into the body there could be effects, distant from the wound, upon all the cells that are sensitive to MFG-E8, which could lead to excess repair of the skin causing aberrant scars named keloids. The major advantage [of this treatment] is that we only administer reprogrammed cells, and we find that they are capable of creating the environment needed to accelerate scar formation. We have indeed discovered the unbelievable potential of the macrophage to make healing possible by simple ex vivo treatment."

What now remains to be done is to test this personalized treatment using human cells. Thereafter, the goal will be to develop a program of human cell therapy for diabetic patients and for victims of severe burns. It will take several years of research before this stage can be reached.

This advanced personalized treatment could also make all the difference in treating cases of challenging wounds. According to the World Health Organization, diabetes affects 8.5% of the global population, and amputation rates of the lower extremities are 10 to 20 times higher in diabetics. "If, with this treatment, we can succeed in closing wounds and promoting healing of diabetic ulcers, we might be able to avoid amputations," Dr. Cailhier said.

"Serious burn victims could also benefit," he added. "By accelerating and streamlining the healing of burns, we may be able to reduce the infections and keloids that unfortunately develop much too often in such patients." Cancer patients requiring extensive reconstruction surgery could also benefit, he said.

Explore further: Macrophages need two signals to begin healing process

More information: Patrick Laplante et al, MFG-E8 Reprogramming of Macrophages Promotes Wound Healing by Increased bFGF Production and Fibroblast Functions, Journal of Investigative Dermatology (2017). DOI: 10.1016/j.jid.2017.04.030

Journal reference: Journal of Investigative Dermatology

Provided by: University of Montreal Hospital Research Centre (CRCHUM)

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Healing wounds with cell therapy - Medical Xpress

Adaptimmune Therapeutics (ADAP) Begins Study to Evaluate … – StreetInsider.com

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Adaptimmune Therapeutics plc (Nasdaq: ADAP), a leader in T-cell therapy to treat cancer, today announced that it has initiated its study of NY-ESO SPEAR Tcells targeting NY-ESO in combination with KEYTRUDA (pembrolizumab), an anti-PD-1 inhibitor marketed by Merck & Co., Inc., Kenilworth, NJ, USA (known as MSD outside the US and Canada), in patients with multiple myeloma. This study is now open for enrollment.

This is Adaptimmunes third clinical trial to initiate within the past month. The Company recently announced the initiation of clinical studies with its wholly-owned SPEAR T-cells targeting AFP in hepatocellular carcinoma, as well as its wholly-owned SPEAR T-cells targeting MAGE-A4 in seven malignant solid tumors.

We are excited to initiate this study as we have already seen encouraging data in a previous singleagent study of NYESO SPEAR T-cells in patients with advanced myeloma in the context of stem cell transplantation, said Rafael Amado, Adaptimmunes Chief Medical Officer. KEYTRUDA has also shown preliminary evidence of activity in multiple myeloma in combination, and there is preclinical evidence to support the view that the combination of NY-ESO SPEAR T-cells and anti-PD-1 therapy may lead to meaningful antitumor activity.

This is an open-label, randomized pilot study designed to evaluate the safety and anti-tumor activity of Adaptimmunes NY-ESO therapeutic candidate alone or in combination with KEYTRUDA in patients who are HLA-A*02 positive and have relapsed and refractory multiple myeloma expressing NY-ESO-1 and/or LAGE1a. The study will enroll up to 20 patients. The primary objective of the study is to evaluate the safety and tolerability of NY-ESO SPEAR T-cell therapy alone or in combination with KEYTRUDA. Additional objectives include antitumor activity, persistence of genetically modified cells in the body, and evaluation of the phenotype and functionality of genetically modified cells isolated from peripheral blood or tumor post infusion.

Adaptimmune is developing the NY-ESO SPEAR T-cell program under a strategic collaboration agreement with GSK.

Clinical Trial Collaboration Agreement for use of KEYTRUDA

Adaptimmune has a clinical trial collaboration agreement with Merck & Co., Inc., Kenilworth, NJ, USA for the use of KEYTRUDA in this study. The agreement is between Adaptimmune and Merck & Co., Inc., Kenilworth, NJ, USA, through a subsidiary. Under the agreement, the trial will be sponsored by Adaptimmune. The agreement also includes provision for potential expansion to include Phase III registration studies in the same indication. Additional details were not disclosed.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

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Old drug points to promising new direction for treatment of autism – Medical News Today

A small trial involving 10 boys with autism spectrum disorder showed promising results from treatment with a drug called suramin, which was originally developed 100 years ago to treat African sleeping sickness, a parasitic disease. Boys who received a single dose of the drug showed measurable, though not permanent, improvements in autism spectrum disorder symptoms.

A report on the trial - led by the University of California-San Diego (UCSD) - is published in the Annals of Clinical and Translational Neurology.

Autism spectrum disorder (ASD), or autism, is a developmental disability with a cluster of behavioral symptoms that typically surface in childhood and generally affect social interaction and communication.

ASD is considered a complex, wide-spectrum disorder because the many symptoms can vary in combination and intensity. For this reason, no two people with ASD will have exactly the same symptoms.

Some of the behavioral symptoms of ASD include:

According to the Centers for Disease Control and Prevention (CDC), ASD affects around 1 in 68 children in the United States and occurs in all socioeconomic, racial, and ethnic groups. However, it is about 4.5 times more common in boys than in girls.

There is no single cause of ASD, but it is thought that a combination of genetic and environmental factors is involved, ranging from pollutants to viral infections and pregnancy complications.

Robert K. Naviaux, a professor of medicine, pediatrics, and pathology at UCSD School of Medicine and first author of the new study, believes that the idea of an abnormal "cell danger response" may offer a unifying theory for the development of ASD.

The cell danger response is a normal signal sent out by all cells when they suffer injury or stress. Its purpose, says Prof. Naviaux, "is to help protect the cell and jump-start the healing process." The signal causes the cell to stiffen its cell walls, stop talking to other cells, and withdraw until the threat subsides.

However, Prof. Naviaux explains that the cell danger response "can get stuck" and stop the completion of the cell's healing cycle. The cell persists in the threat response state, which can "permanently alter the way the cell responds to the world."

The effect at the molecular level is to disrupt the chemistry of cell equilibrium and cause chronic disease. Prof. Naviaux says that "when this happens during early child development, it causes autism and many other chronic childhood disorders."

Cells activate the cell danger response by releasing a small molecule from their energy-making compartments, or mitochondria. The release of this molecule is what acts as the danger signal, and it keeps being released as long as the cell danger response is active.

Suramin blocks the ability of the small molecule to release the danger signal. The effect, says Prof. Naviaux, is to signal that "the cellular war is over, the danger has passed and cells can return to 'peacetime' jobs like normal neurodevelopment, growth, and healing."

The drug was originally developed in 1916 by the German firm Frederich Bayer and Co. for treating diseases caused by trypanosome parasites, such as those that cause African sleeping sickness and river blindness.

For their small study - which took the form of a randomized, double-blind, placebo-controlled phase I/II clinical trial involving 10 boys, all aged between 5 and 14, who were diagnosed with ASD - the team tested the effect of a single dose of suramin on symptoms of ASD.

The aim of the trial was to find out whether the cell danger response theory might explain the development of ASD and to assess the safety of suramin, which is not approved for the treatment of ASD. An earlier trial that tested the drug on mice had found that a single dose "temporarily reversed" symptoms of ASD.

The boys were randomly assigned to receive either a single intravenous transfusion of suramin, or a placebo.

The results showed that all five boys who received the active drug showed measurable improvements in ASD symptoms not seen in the placebo group. The improvements were specifically in speech and language, social communication and play, coping skills, calm and focus, and repetitive behavior.

The researchers used a battery of standardized tests and interviews to measure the improvements. When these involved parent observations, the team only counted a change as an improvement if it persisted for at least a week. This was to rule out any fluctuations in day-to-day behavior that may have occurred anyway.

Prof. Naviaux says that there were four non-verbal children in the trial: two aged 6 and two aged 14, with one of each age having been assigned to the drug group and the placebo group.

"The 6-year-old and the 14-year-old who received suramin said the first sentences of their lives about one week after the single suramin infusion," he notes. "This did not happen in any of the children given the placebo."

The team reports that while the children were on suramin, there was a dramatic improvement in the benefits they derived from the speech therapy, occupational therapy, and other programs that they were taking part in.

However, the effects of the drug waned over time. The measured improvements peaked and then gradually dwindled after a few weeks.

The team is not dispirited by this. They say that the findings are sufficient to show that it is worth testing different doses of suramin in larger, more diverse groups of people with ASD, over longer periods. This could help to establish how long improvements last, and also whether side effects other than the mild skin rash observed in the small trial might emerge.

Andrew W. Zimmerman, a clinical professor of pediatrics and neurology at UMass Memorial Medical Center, was not involved in the trial but is also researching in a similar field. He says that the results of the trial are "encouraging for the field of autism," both in terms of the promising changes in the children and also because it supports the cell danger response theory. He comments:

"As the authors point out, many genetic variants have been found in ASD, but few have led to specific treatments. The CDR [cell danger response] includes a number of metabolic pathways that may be affected by a number of genetic mutations or by environmental factors that have effects epigenetically - beyond the genes themselves."

Prof. Naviaux and colleagues point out that suramin is not approved for the treatment of autism. They strongly urge against using it in unauthorized settings. The drug must undergo years of rigorous testing through clinical trials to identify any rare side effects and establish safe doses.

Learn how a new biochemical method accurately diagnosed autism in children.

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Old drug points to promising new direction for treatment of autism - Medical News Today

Therapy Focus – Not Quite The Hammer For Sickle Cell Disease – Seeking Alpha

When it comes to serious diseases with virtually no treatments the US FDA has shown flexibility in approving new therapies, even if these have questionable efficacy. This could play out again when the agency decides on Emmaus' Endari for sickle cell disease by July 7, especially as the project now has an adcom's blessing.

The case of Endari is curious for several reasons, not least the fact that it has a cheaply available active ingredient and a data package flattered by statistical changes; its maker until recently looked like being taken over by the struggling Generex (OTCPK:GNBT) (OTCPK:GNBTD). Still, given how barren the industry's sickle cell disease pipeline is, patients might welcome any advance, however speculative (see table below).

As such, the US adcom's 10-3 vote in support of Endari's risk/benefit profile is understandable. This came despite questions at the meeting about a high rate of dropouts, missing data in the project's pivotal GLUSCC09-01 study, and doubts about the relevance of the primary endpoint - reduction of sickle cell crises over 48 weeks.

Perhaps most egregious of all was that Endari failed according to the trial's planned analysis, yielding a non-significant p value of 0.063 versus the control comparator, maltodextrin. It was only when Emmaus amended the statistical method that it claimed success with a 0.005 p value (Upcoming events - Panel woes for Puma and statistical uncertainties for Emmaus, May 12, 2017).

A low bar

Still, if Endari is approvable, competitors might celebrate the fact that the bar in sickle cell disease has been set so low.

Perhaps the most important near-term challenge will come from Glycomimetics' (NASDAQ:GLYC) rivipansel, a pan-selectin antagonist, given that this was licensed to Pfizer, which is now in charge of a phase III trial called Reset.

Sickle cell disease is an autosomal recessive disorder caused by a simple mutation in the gene coding for hemoglobin, which affects hemoglobin's ability to carry oxygen and causes it to polymerize. These hemoglobin polymers distort red blood cells' shape and increase their rigidity, leading to anemia, occluded blood flow and pain crises during severe episodes.

Sickle cell disease is curable with stem cell transplantation, but most patients do not have a matched donor to serve as the graft source. Two groups, Gamida Cell and Bellicum (NASDAQ:BLCM), are working on expanded grafts that might be used by non-matched or partially matched patients.

Clearly, this is complex, but unlike stem cells few small-molecule or antibody approaches will treat the disease's underlying cause. The aim with rivipansel, for instance, is to reduce adhesion of red blood cells, thus making it harder for them to aggregate.

Also acting via anti-adhesive properties is Modus Therapeutics' Sevuparin, a phase II asset that has been licensed to Ergomed. Endari is similarly a symptom-targeting agent, aiming to reduce oxidative damage to cells, while Eliquis is being studied for its anticoagulant effects.

In terms of potential cures the spotlight is on Bluebird's (NASDAQ:BLUE) gene therapy Lentiglobin, which aims to correct the disease's underlying genetic defect. Both this and Global Blood Therapeutics' GBT440, which inhibits hemoglobin polymerization, have had rollercoaster developments, and updates will be presented at December's Ash meeting.

It is also worth noting that data generated by Selexys' crizanlizumab, an antibody targeting cell adhesion, were good enough to secure a buyout by Novartis (NYSE:NVS) (Ash delivers early for Selexys, November 21, 2016).

Will it sell?

All that said, in the near term Emmaus faces a more fundamental threat: it is by no means certain that Endari is a viable business proposition.

Its active ingredient is a pharmaceutical-grade form of L-glutamine, which is available over the counter; it is also available on prescription as Nutrestore for short bowel syndrome. Approval for sickle cell disease would lock out competitors on the basis of data exclusivity, but getting insurance coverage could be tricky, especially in a price-conscious political environment.

Then there is the mystery of Emmaus' proposed takeover by the troubled oral insulin company Generex. This was to have involved Generex buying a 51% stake at a $441m valuation, under a letter of intent signed in January, but the deal was quietly terminated on May 16.

Among the unusual aspects of this transaction was the $500,000 cash advanced to Generex by its chief executive and a senior vice-president to cover the up-front fee under the letter of intent. Generex then raised $3m, and paid $3.5m to Emmaus in March, but scrapped the deal citing delays in its plan to eliminate warrants and preferred stock and carry out a reverse split.

Generex says it is now due a $4m refund. It seems that the group will not, after all, become a player in sickle cell disease.

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