Stem Cell Clinic

In small study, hints of promise for ‘natural killer’ cell therapy – BioPharma Dive

A new type of cancer cell therapy could avoid some of the serious side effects commonly associated with CAR-T treatments, and possibly offer an easier path to developing "off-the-shelf" treatments, suggest findings from a small study led by researchers at the MD Anderson Cancer Center in Houston, Texas.

The results, which were published Wednesday in the New England Journal of Medicine, are from just 11 patients. Other factors, such as the use of postremission therapy, limit what conclusions can be drawn about the researchers' approach, which relies on "natural killer" cells rather than the T cells used in cellular drugs like Novartis' Kymriah.

Still, the data offer a glimpse into why Japanese drugmaker Takedaagreed last November to license the CAR NK cell therapy from MD Anderson, part of the company's broader push into cell and gene treatments. Some of the data published Wednesday was previously disclosed by the pharma.

The success of cancer immunotherapy, of which CAR-T treatments are a major part, has put T cells at the center of a now decade-long research revival in oncology.

But T cells are only one component of the body's immune system, and scientists in academia and in biotech are exploring whether other cellular defenders could be similarly recruited.

Researchers at MD Anderson have turned to natural killer cells, which by design recognize and attack cancers or other invaders. Such cells have been tested as an anti-cancer treatment before,but using genetic engineering to improve their tumor-killing properties, which the MD Anderson team has done, is a newer innovation.

"To my knowledge, this is the largest body of evidence on the use of CAR NK cells in patients with cancer," said Katayoun Rezvani, the study's corresponding author and a professor of stem cell transplantation and cellular therapy at MD Anderson, in an interview.

Using NK cells derived from cord blood, Rezvani and her colleagues engineered the cells to express a receptor for a protein called CD19, commonly found on the surface of B-cell malignancies like leukemia and lymphoma. They also added a gene for interleukin-15 to boost the expansion and persistence of the infused NK cells, which without engineering would typically disappear after about two weeks.

While the CAR-T treatments Kymriah (tisagenlecleucel) and Yescarta (axicabtagene ciloleucel) also target CD19, they are made from a patient's own T cells, which are extracted and then engineered outside the body. The personalized process is time-consuming and laborious, hampering the commercial uptake of both Kymriahand Yescarta.

By using cord blood, Rezvani and her team are pursuing an allogeneic, or "off-the-shelf," approach to cell treatment something many consider to be the next step for the field.

Initial data look promising. Seven of the 11 treated patients, who had either chronic lymphocytic leukemia or non-Hodgkin lymphoma, responded to treatment, with the cancers of three going into remission.Most notably, none experienced cytokine release syndrome or neurotoxicity, two severe side effects that commonly occur in patients treated with CAR-T therapy.

"The lack of toxicity is very exciting here," wrote Stephan Grupp, an oncologist at Children's Hospital of Philadelphia and a leader in the CAR-T field, in comments emailed to BioPharma Dive. He was not involved with the MD Anderson study.

"We really think that this is something inherent to the biology of the natural killer cells, which means their profile of toxicity is different than that of T cells,"Rezvanisaid.

Study participants did have blood toxicities that researchers associated with the chemotherapy given prior to infusion of the CAR NK cells.

While positive, the results are limited by several factors which make drawing broader conclusions about the ultimate potential of the treatment difficult.

Five of the seven responding patients received postremission treatment, including stem cell transplants, Rituxan (rituximab) and Revlimid (lenalidomide), so researchers did not assess the duration of response to CAR NK therapy.

Additionally, a fresh CAR NK cell product was manufactured for each patient in this study, rather than using the cord blood to produce multiple therapies as would be envisioned for a true off-the-shelf product.

"I think the potential for this approach to be 'off-the-shelf' is also a little speculative at this time," wrote Grupp.

"We would need to see multiple patients treated from the same expanded product with no HLAmatching to know if 'off-the-shelf' is going to be part of the story here," he added, referring to the process by which patients are matched to donor cells.

If cord blood-derived CAR NK cells were able to be given without matching to a patient's HLA genotype, any resulting treatment could be used more widely. Nine patients were partially matched in the MD Anderson study, while the last two were treated without consideration of HLA type.

The MD Anderson researchers plan to continue enrolling patients in the study and are working with Takeda to design a larger, multi-center trial.

The drugmaker is planning to advance the treatment, which it licensed and now calls TAK-007, into pivotal studies in two types of lymphoma and CLL by 2021, with a potential filing for approval in 2023.

"Targeting CD19 was a proof of concept and now that we've demonstrated that this CAR NK approach can work and is safe we want to use this platform to target other types of cancers," said Rezvani, indicating interest in multiple myeloma and acute myeloid leukemia.

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In small study, hints of promise for 'natural killer' cell therapy - BioPharma Dive

Maybe Memorizing the Krebs Cycle Was Worthwhile After All – Medscape

Like most medical students, I struggled to memorize the Krebs cycle, the complex energy-producing process that takes place in the body's mitochondria. Rote learning of Sir Hans Krebs' eponymous cascade of reactions persists and has been cited as a waste of time in modern medical education. However, it looks like that specialized knowledge about mitochondrial structure and function may finally come in handy in the clinic.

Advances in genetics have contributed to improved diagnostic accuracy of a diverse spectrum of mitochondrial disorders. Respiratory chain, nuclear gene, and mitochondrial proteome mutations can lead to multisystem or organ-specific dysfunction.

A new potential treatment for mitochondrial disorders, elamipretide, has received orphan drug designation from the US Food and Drug Administration (FDA) and is in clinical trials sponsored by Stealth Biotherapeutics. [Dr Wilner has consulted for Stealth Biotherapeutics.] Recently I had the opportunity to interview Hilary Vernon, MD, PhD, associate professor of genetic medicine at Johns Hopkins University, Baltimore, Maryland, and an expert on mitochondrial disorders. Dr Vernon discussed her research on elamipretide as a treatment for Barth syndrome, a rare form of mitochondrial disease.

I am the director of the Mitochondrial Medicine Center at Johns Hopkins Hospital. I work with individuals from infancy through adulthood who have mitochondrial conditions. I became interested in this particular area when I was early in my pediatrics/genetics residency at Johns Hopkins and saw the toll that mitochondrial disorders took on patients' lives and the limited effective therapies. At that point, I decided to focus on patient care and research in this area.

Mitochondrial disorders can be difficult to recognize because of their inherent multisystem nature and variable presentations (even between affected members of the same family). However, there are several considerations that should raise a clinician's suspicion for a mitochondrial condition. Ascertaining a family history of disease inheritance through the maternal line can raise the suspicion for a mitochondrial DNA disorder. Identification of a combination of medical issues in different organ systems that are seemingly unrelated in an individual (ie, optic atrophy and muscle weakness or diabetes and hearing loss) can also raise suspicion for a mitochondrial condition.

Due to the nature of mitochondria as the major energy producers of the cells, high-energy-requiring tissues such as the brain and the muscles are often affected. Perhaps the best known mitochondrial diseases to neurologists are MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke) as well as MERFF (myoclonic epilepsy with ragged red fibers). There is a nice body of literature on the effects of arginine and citrulline in modifying stroke-like episodes in MELAS, and this is a therapy that is in current practice.

Mitochondria are complex organelles whose structure and function are encoded in hundreds of genes originating from both the nucleus of the cell and the mitochondria themselves. Mitochondria have many key roles in cellular function, including energy production through the respiratory chain, coordination of apoptosis, nitrogen metabolism, fatty acid oxidation, and much more.

Various cofactors and vitamins can be employed to improve mitochondrial function for different reasons. For example, if a specific enzyme is dysfunctional, supplying the cofactor for that enzyme may improve its function (ie, pyruvate dehydrogenase and thiamine). Antioxidants have also been considered to help reduce the oxidant load that could potentially cause ongoing damage to the mitochondrial membrane resulting from respiratory chain dysfunction (ie, coenzyme Q-10).

It is important to remember that the highest number of individual mitochondrial disorders result from mutations in genes located in the nuclear DNA. For example, the TAZ gene that is abnormal in Barth syndrome is a nuclear gene located on the X chromosome. These genes are amenable to the "regular" approaches to gene therapy.

Targeting mitochondrial DNA for gene therapy requires a different set of approaches because the gene delivery has to overcome the barrier of the mitochondrial membranes. However, research is ongoing to overcome these obstacles.

Barth syndrome is a very rare genetic X-linked disorder that usually only affects males. The genetic defect leads to an abnormal composition of cardiolipin on the inner mitochondrial membrane. Cardiolipin is an important phospholipid involved in many mitochondrial functions, including organization of inner mitochondrial membrane cristae, involvement in apoptosis, and organization of the respiratory chain (which is responsible for producing ATP via the process of oxidative phosphorylation), and many of these functions are abnormal in Barth syndrome. Individuals with Barth syndrome typically have early-onset cardiomyopathy, myopathy, intermittent neutropenia, fatigue, poor early growth, among other health concerns.

Early in my post-residency career, I followed several patients with Barth syndrome and was quickly welcomed into the Barth syndrome community by the families and the Barth Syndrome Foundation. From there, I founded the only interdisciplinary Barth syndrome clinic in the US and began to focus a significant amount of my clinical and laboratory research on this condition.

Most commonly, these individuals come to medical attention because of cardiomyopathy, but a minority of patients do come to attention due to repeated infections and neutropenia. Patients were identified for study participation through the Barth Syndrome Foundation or because they were already patients of my study team.

All participants were known to have Barth syndrome prior to study entry, and all had confirmatory genetic testing showing a pathogenic mutation in the TAZ gene.

By binding to cardiolipin in the inner mitochondrial membrane, elamipretide is believed to stabilize cristae architecture and electron transport chain structure during oxidative stress. I thought it would be great if this could help to stabilize the abnormal cardiolipin components on the inner mitochondrial membrane in Barth syndrome.

We observed improvements in several areas across the study population in the open-label extension part of the study. This includes a significant improvement in exercise performance (as measured by the 6-minute walk test, with an average improvement of 95.9 meters at 36 weeks) and a significant improvement in muscle strength. We also observed a potential improvement in cardiac stroke volume. Most of the adverse events were local injection-site reactions and were mild to moderate in nature.

The TAZPOWER trial has an ongoing open-label extension with the same endpoints as the placebo-controlled portion evaluated on an ongoing basis. In addition, in my laboratory, we are using induced pluripotent stem cells to learn more about how cardiolipin abnormalities affect different cell types in an effort to understand the tissue specificity of disease. This will help us to understand whether different aspects of Barth syndrome would necessitate individual management or clinical monitoring strategies.

Mitochondrial inner membrane dysfunction is increasingly recognized as a major aspect of the pathology of a wide range of mitochondrial conditions. Therefore, based on the role of stabilizing mitochondrial membrane components, elamipretide has a potential role in many disorders of the mitochondria.

Yes, this is what we would call "secondary mitochondrial dysfunction" (meant to differentiate from "primary mitochondrial disease," which is caused by defects in genes that encode for mitochondrial structure and function). Approaches intended to protect the mitochondria from further damage, such as antioxidants or strategies that can bypass the mitochondria for ATP production, could overlap as treatment for primary mitochondrial disease and secondary mitochondrial dysfunction.

This is something that is much discussed as a newer consideration for families who are affected by disorders of the mitochondrial DNA, but not something I have experience with firsthand.

Yes. The United Mitochondrial Disease Foundation and the Mitochondrial Medicine Society collaborated to develop the Mito Care Network, with 19 sites identified as Mitochondrial Medicine Centers across the US.

Andrew Wilner is an associate professor of neurology at the University of Tennessee Health Science Center in Memphis, a health journalist, and an avid SCUBA diver. His latest book is The Locum Life: A Physician's Guide to Locum Tenens.

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Maybe Memorizing the Krebs Cycle Was Worthwhile After All - Medscape

Global Personalized Medicine Market Analysis (2016 to 2026) – Total Market Value is Expected to Reach $3.92 Trillion by 2026 – ResearchAndMarkets.com…

The "Global Personalized Medicine Market Analysis 2019" report has been added to ResearchAndMarkets.com's offering.

The Global Personalized Medicine market is expected to reach $3.92 trillion by 2026 growing at a CAGR of 12.1% during the forecast period.

The efficient and advanced technology and Higher prevalence of disease are driving the market growth. However, the higher cost of research and developments is hampering the market.

Key Questions Answered in this Report:

Based on the End User, the hospital's segment is estimated to have a lucrative growth due to the lower cost personalized medicines availability in the hospitals.

As the practice of personalized medicine becomes more widespread, hospitals will also experience the need to adapt. That does not mean every hospital and medical centre should try and drive the science, but they should be open to collaborations to facilitate such work.

Key Topics Covered:

1 Market Synopsis

2 Research Outline

2.1 Research Snapshot

2.2 Research Methodology

2.3 Research Sources

2.3.1 Primary Research Sources

2.3.2 Secondary Research Sources

3 Market Dynamics

3.1 Drivers

3.2 Restraints

4 Market Environment

4.1 Bargaining power of suppliers

4.2 Bargaining power of buyers

4.3 Threat of substitutes

4.4 Threat of new entrants

4.5 Competitive rivalry

5 Global Personalized Medicine Market, By Product

5.1 Introduction

5.2 Diagnostics

5.3 Personalized Medical Care

5.4 Personalized Nutrition & Wellness

5.5 Therapeutics

6 Global Personalized Medicine Market, By Technology

6.1 Introduction

6.2 Metabolomics

6.3 Pharmacodynamics

6.4 Pharmacogenetics

6.5 Pharmacogenomics

6.6 Pharmacokinetics

6.7 Pharmacoproteomics

6.8 Point-of-Care Testing

6.9 Stem Cell Therapy

7 Global Personalized Medicine Market, By Therapeutic Area

7.1 Introduction

7.2 Autoimmune Diseases

7.3 Blood Transfusion Safety

7.4 Cancer Management

7.5 Cardiovascular Diseases (CVD)

7.6 Central Nervous System (CNS) Disorders

7.7 Coagulation Therapy

7.8 Diabetes

7.9 Infectious Diseases

7.10 Antiviral

7.11 Neurology

7.12 Psychiatry

7.13 Oncology

7.14 Immunology

7.15 Respiratory

8 Global Personalized Medicine Market, By Distribution Channel

8.1 Introduction

8.2 Dietary Care Centers

8.3 Hospital's Pharmacies

8.4 Retail Pharmacies

8.5 Other Distribution Channels

9 Global Personalized Medicine Market, By Application

9.1 Introduction

9.2 Biomarker Identification

9.3 Clinical Research Applications

9.4 Companion Diagnostics

9.5 Health Informatics

10 Global Personalized Medicine Market, By End-User

10.1 Introduction

10.2 Academic Institutes

10.3 Bio and Health Informatics Companies

10.4 Clinical Care and Research Laboratories

10.5 Contract Research Organizations

10.6 Hospitals

10.7 Molecular Diagnostic Laboratories and Testing Facilities

10.8 Research Laboratories

10.9 Service Providers

10.10 Partner

10.11 Venture Capitalists

10.12 Other End Users

11 Global Personalized Medicine Market, By Geography

11.1 North America

11.2 Europe

11.3 Asia Pacific

11.4 South America

11.5 Middle East & Africa

12 Strategic Benchmarking

13 Vendors Landscape

13.1 Abbott Laboratories

13.2 Affymetrix Incorporated

13.3 Agendia N.V

13.4 Agilent Technologies, Inc

13.5 Amgen, Inc

13.6 Asuragen Incorporated

13.7 Bayer Healthcare Pharmaceuticals, Llc

13.8 Celera Diagnostics LLC

13.9 Celgene Corporation

13.10 Roche Diagnostics Corporation

13.11 Precision Biologics Incorporated

13.12 Siemens Healthcare Diagnostics, Inc

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Global Personalized Medicine Market Analysis (2016 to 2026) - Total Market Value is Expected to Reach $3.92 Trillion by 2026 - ResearchAndMarkets.com...

Hyperbaric oxygen therapy can improve cardiac function in healthy, aging – The Jerusalem Post

Hyperbaric oxygen therapy (HBOT) can improve heart functionality in healthy aging humans, according to a study by the Sagol Center for Hyperbaric Medicine and Research at Shamir Medical Center in Beer Yaacov.In this study, director of the Sagol Center for Hyperbaric Medicine and Research at Shamir Medical Center Prof. Shai Efrati and Dr. Marina Leitman, head of the Echocardiography Unit and Noninvasive Cardiology Service at Shamir Medical Center, turned their attention to HBOTs impact on cardiac function.According to the center, the study of HBOT for cardiac function has been limited, mostly evaluating patients during and after short-term exposures. However, for the first time, the study was conducted in humans and it demonstrated that repetitive HBOT protocols have a sustained effect on heart function.Healthy patients receiving HBOT to improve cognitive function underwent a 60-session treatment course using the Sagol Centers regenerative HBOT protocols. Using a high-resolution echocardiography, 31 patients were evaluated before HBOT was administered and three weeks after treatment concluded to identify the sustained effect of the treatment.HBOT includes the inhalation of 100% oxygen at pressures exceeding one atmosphere absolute [ATA], which is the average atmospheric pressure exerted at sea level, in order to increase the amount of oxygen dissolved in the body tissues, Efrati told The Jerusalem Post.Efrati, who has been pioneering new approaches for the application of HBOT treatments that specifically focus on HBOTs ability to trigger regeneration in the body, said that in the past HBOT was used mostly to treat chronic non-healing wounds.In recent years, there is growing evidence on the regenerative effects of HBOT, he said. We have now realized that the combined action of both hyperoxia (an excess of oxygen in the body) and hyperbaric pressure, leads to significant improvement in tissue oxygenation while targeting both oxygen and pressure sensitive genes, resulting in improved mitochondrial metabolism with anti-apoptotic (anti-cell death) and anti-inflammatory effects.According to Efrati, the newly developed protocols used in this study, which includes the intermittent increasing and decreasing of oxygen concentration, induces what is known as the Hyperoxic Hypoxic Paradox.This, he said induces stem cells proliferation and mobilization, leading to the generation of new blood vessels (angiogenesis) and tissue regeneration.Efrati said that during the first studies they conducted at the Sagol Center, they evaluated the beneficial effects of HBOT in treating traumatic brain injury and stroke. However, in this study we evaluated for the first time the effect of these new regenerative HBOT protocols on the normal aging heart. For the first time in humans we have demonstrated that HBOT can improve cardiac function.Efrati said for the last 12 years his team has developed an ongoing research program that investigates the regenerative effects of HBOT on different issues and degrees of damage. At the beginning we were focused on non-healing peripheral wounds. Then, we turned our focus to certain types of brain injuries.However, once the researchers found that HBOT induced many of the essential elements crucial to repairing almost any mechanism, we initiated a complementary research program that targets other organs such as the heart and other elements related to expected age-related functional decline.Along with normal aging, there is typically a decrease in cardiac function particularly in the mitochondrial cells of the heart, Efrati said.The mitochondria are the powerhouse of the cell [and] this is where we create energy, he said. HBOTs ability to improve mitochondrial function may explain the beneficial effects that we saw in the cardiac function of this normal aging population.By exposing the mitochondria to the fluctuations in oxygen by the use of HBOT, the team observed an improvement in contractility function of the heart meaning, the heart muscle contracted more efficiency over the course of the 60-session protocol.Efrati said the effect was particularly evident in the left ventricle, which is the chamber responsible for pumping oxygenated blood to the rest of the body.This is only the beginning of our understanding of the impact of HBOT on cardiac function in a normally aging population, and a larger and more diverse cohort will be required to further evaluate our initial findings, he said.Asked whether this treatment could also be used on people who are predisposed to heart conditions, Efrati said the short answer is yes, but he stressed that more research is needed.As far as we know, we are the first to identify HBOTs ability to improve cardiac function, Efrati said. Our study was on a group of 31 asymptomatic normal aging heart patients.We believe it is important to expand the scope of this study to a larger group, with both symptomatic and asymptomatic patients to understand the possibilities for HBOT as a treatment for patients with heart-related diseases, he said.The Sagol Center has also been studying the impact of HBOT on a variety of cognitive conditions.We have also conducted studies which showed positive results for the treatment of post-concussion syndrome as a result of traumatic brain injury, post-stroke recovery, fibromyalgia, Efrati said, adding that today, medical professionals understand that fibromyalgia is linked to issues in the brain center responsible for pain interpretation.Not every patient will benefit from HBOT, which is why patient selection should be done very carefully based on the damage seen in brain imaging assessments, he said.For example, if someone has a stroke, some of the tissue at the core of the stroke will die we will not be able to recover this tissue, Efrati said. But, other tissue that is damaged but not fully dead... is where HBOT can help.This damaged tissue, known as the metabolic dysfunction tissue (penumbra), is where we can have an impact and help recover lost function, he said.On the time line as to when using HBOT protocols may be put into effect on healthy aging patients in Israel, Efrati said these studies are already ongoing.I cant speak too much about this, as we are in the process of developing the results of the first study for publication, he said. However, we believe HBOT can positively impact both cognitive and physical performance in aging adults based on what we have seen at this point.Efrati said they will continue pursuing this line of research as it has the ability to transform how we look at aging.A number of research collaborations are ongoing, including research on cognitive decline, fibromyalgia and PTSD, he said.In addition, we have an ongoing research program on athletic performance both in professional and amateur level athletes, which looks at how HBOT may further improve performance, he said. Finally, we are studying the impact of HBOT on healthy aging adults to understand how HBOT may improve our health and cognitive performance as we age.When you look at aging as a disease that can be measured, then it can be treated, and this is a serious area of investigation for us, Efrati said.The study, led by Dr. Marina Leitman, Dr. Shmuel Fuchs, Dr. Amir Hadanny, Dr. Zvi Vered and Efrati, was published in the International Journal of Cardiovascular Imaging.

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Hyperbaric oxygen therapy can improve cardiac function in healthy, aging - The Jerusalem Post

Will Dialysis Become a Thing of the Past? – Jewish Link of New Jersey

By Ken Stephens | February 06, 2020

A groundbreaking study has shown that it is possible to rejuvenate damaged kidneys and improve their function, a procedure that could reverse chronic kidney disease, offsetting the need for dialysis. This is the first breakthrough in decades to combat this disease, often precipitated by hypertension and diabetes, and which affects a whopping 10% of the population worldwide.

The study was conducted by Professor Benjamin Dekel, head of Pediatric Nephrology and the Pediatric Stem Cell Research Institute in the Edmond and Lily Safra Childrens hospital at Sheba Medical Center, and published this week in the prestigious Cell Reports medical journal.

In past studies, researchers discovered that the adult kidney constantly renews itself over time through the activity of colonies of cells that replace lost and degenerated cells in the kidney. Prof. Dekel and his team have now developed an innovative technology that involves the extraction of such healthy kidney cells from diseased kidneys. These cells are then expanded into large numbers within a laboratory environment. By generation of three-dimensional cultures called kidney spheres, the cells show improved function to generate new kidney tissue and replace lost cells. The new cells are then reintroduced into the kidney where they rebuild it, positively influencing neighboring cells and improving its function (see diagram).

One of the most significant aspects of the discovery is that the newly developed technology uses the patients own cells, thereby circumventing the need for immunosuppression as well as problems associated with immune rejection.

Thus far, the method has been tested on mice, where the cells have shown their ability to generate new renal structures, associated with an ability to be retained for a long time once administered into the host kidney. The treated mice displayed improved renal function.

By focusing on improving and stabilizing renal function, this treatment has the potential to help millions of patients with chronic kidney disease and who have yet to require dialysis treatment.

These astounding results will be studied in clinical trials on patients with renal failure by the KidneyCure Bio firm, which commercialized this technology.

Prof. Benjamin Dekel, who led the project said, The breakthrough in this technology, which was developed at the Sheba Medical Center, is not only in the ability to maintain the kidney-renewing cells outside the body, but also in the ability to multiply them and generate large numbers of cells and make them function properly using the 3-D cultures. This is important news for patients with chronic kidney disease, who hopefully will benefit from these discoveries in the coming years. The ability to generate new kidney tissue (to replace the damaged tissue) could help millions of patients worldwide who suffer from kidney disease.

The trailblazing research was carried out by senior researchers Dr. Orit Harari-Steinberg, Dr. Dorit Omer, and Ms. Yehudit Gnatek from the Pediatric Stem Cell Research Institute, under the leadership of Prof. Dekel.

Collaborators include: Dr. Zohar Dotan, Head of Uro-Oncology Service from the urology department at Sheba Medical Center; Dr. Tomer Kalisky and co-workers from Bar Ilan University; and Prof. Yaron Fuchs and co-workers from The Technion.

By Ken Stephens

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Will Dialysis Become a Thing of the Past? - Jewish Link of New Jersey