Pericardial Injection Effective, Less Invasive Way to Get Regenerative Therapies to Heart – NC State News

Injecting hydrogels containing stem cell or exosome therapeutics directly into the pericardial cavity could be a less invasive, less costly, and more effective means of treating cardiac injury, according to new research from North Carolina State University and the University of North Carolina at Chapel Hill.

Stem cell therapy holds promise as a way to treat cardiac injury, but delivering the therapy directly to the site of the injury and keeping it in place long enough to be effective are ongoing challenges. Even cardiac patches, which can be positioned directly over the site of the injury, have drawbacks in that they require invasive surgical methods for placement.

We wanted a less invasive way to get therapeutics to the injury site, says Ke Cheng, Randall B. Terry, Jr. Distinguished Professor in Regenerative Medicine at NCStates Department of Molecular Biomedical Sciences and professor in the NCState/UNC-Chapel Hill Joint Department of Biomedical Engineering. Using the pericardial cavity as a natural mold could allow us to create cardiac patches at the site of injury from hydrogels containing therapeutics.

In a proof-of-concept study, Cheng and colleagues from NCState and UNC-Chapel Hill looked at two different types of hydrogels one naturally derived and one synthetic and two different stem cell-derived therapeutics in mouse and rat models of heart attack. The therapeutics were delivered via intrapericardial (iPC) injection.

Via fluorescent imaging the researchers were able to see that the hydrogel spread out to form a cardiac patch in the pericardial cavity. They also confirmed that the stem cell or exosome therapeutics can be released into the myocardium, leading to reduced cell death and improved cardiac function compared to animals in the group who received only the hydrogel without therapeutics.

The team then turned to a pig model to test the procedures safety and feasibility. They delivered the iPC injections using a minimally invasive procedure that required only two small incisions, then monitored the pigs for adverse effects. They found no breathing complications, pericardial inflammation, or changes in blood chemistry up to three days post-procedure.

Our hope is that this method of drug delivery to the heart will result in less invasive, less costly procedures with higher therapeutic efficacy, Cheng says. Our early results are promising the method is safe and generates a higher retention rate of therapeutics than those currently in use. Next we will perform additional preclinical studies in large animals to further test the safety and efficacy of this therapy, before we can start a clinical trial.

I anticipate in a clinical setting in the future, iPC injection could be performed with pericardial access similar to the LARIAT procedure. In that regard, only one small incision under local anesthesia is needed on the patients chest wall, says Dr. Joe Rossi, associate professor in the division of cardiology at UNC-Chapel Hill and co-author of the paper.

The research appears in Nature Communications and was supported by the National Institutes of Health and the American Heart Association. Dr. Thomas Caranasos, director of adult cardiac surgery at UNC-Chapel Hill, also contributed to the work.

-peake-

Note to editors: An abstract follows.

Minimally invasive delivery of therapeutic agents by hydrogel injection into the pericardial cavity for cardiac repair

DOI: 10.1038/s41467-021-21682-7

Authors: Dashuai Zhu, Zhenhua Li, Ke Cheng, North Carolina State University; Thomas Caranasos, Joseph Rossi, University of North Carolina at Chapel Hill Published: March 3, 2021 in Nature Communications

Abstract: Cardiac patch is an effective way to deliver therapeutics to the heart. However, such procedures are normally invasive and difficult to perform. Here, we developed and tested a method to utilize the pericardial cavity as a natural mold for in situ cardiac patch formation after intrapericardial (iPC) injection of therapeutics in biocompatible hydrogels. In rodent models of myocardial infarction (MI), we demonstrated that iPC injection is an effective and safe method to deliver hydrogels containing induced pluripotent stem cells-derived cardiac progenitor cells (iPS-CPCs) or mesenchymal stem cells (MSCs)-derived exosomes. After injection, the hydrogels formed cardiac patch-like structure in the pericardial cavity, mitigating immune response and increasing the cardiac retention of the therapeutics. With robust cardiovascular regeneration and stimulation of epicardium-derived repair, the therapies mitigated cardiac remodeling and improved cardiac functions post MI. Furthermore, we demonstrated the feasibility of minimally-invasive iPC injection in a clinically-relevant porcine model as well as in human patients. Collectively, our study establishes iPC injection as a safe and effective method to deliver therapeutics to the heart for cardiac repair.

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Pericardial Injection Effective, Less Invasive Way to Get Regenerative Therapies to Heart - NC State News

Biomarkers Help Predict the Role of Chemotherapy in Biologic Aging – OncLive

Biologic aging is a complex process. There are several theories on why and how we age, and it is probable that none of them account for all the aspects. We are constantly exposed to both internal and external stimuli that, over time, facilitate the aging process. These stimuli include ionizing radiation, ultraviolet light, diet, exercise, oxidative stresses, and perhaps, worst of all, smoking. All of these can trigger intracellular processes, including DNA methylation, or epigenetic change, telomere shortening and damage, DNA damage, and mitochondrial dysfunction. These factors accelerate cellular senescencewhat is thought to be the critical factor in aging and has been shown to increase with age.1,2

Cellular senescence is a condition in which a cell has lost the ability to proliferate, and senescent cells increase in almost all organs and tissues as we age. Over time, these changes ultimately lead to the development of significant comorbidities and the cumulative functional deficits we acquire during aging. However, senescent cells are metabolically active and can produce cytokines and inflammatory proteinsthe senescence-associated secretory phenotypefurther accelerating aging and promoting malignancy. FIGURE 1 illustrates the effect of age and insults on senescence.

Accumulation of senescent cells is implicated as a cause of tissue reprogramming, osteoporosis, glaucoma, neurodegeneration, type 2 diabetes, changes in the microbiome, immune system dysfunction, dysfunctional tissue repair and fibrosis, and cancer.3 Recent data have shown the potential role of chemotherapy and radiation therapy in accelerating aging. Nowhere is chemotherapys effect in accelerating aging more apparent than in children and adolescents treated successfully for childhood malignancy.4 In these patients, by the time they reach aged 35 years, approximately 30% have the clinical phenotype of a person aged 65 years, as evidenced by dramatic increases in cardiac disease and new second malignancies.

At the University of North Carolina Lineberger Comprehensive Cancer Center, we have focused on the effects of chemotherapy and accelerated aging in cancer. To date, we have studied the effects of chemotherapy on childhood cancer, early breast cancer, and bone marrow transplantation. Our research has explored the role of p16INK4a expression, a robust marker of biologic aging, following on the work of Norman E. Ned Sharpless, MD, director of the National Cancer Institute. p16INK4a encodes for a protein that blocks cyclin-dependent kinase, analogous to the cyclin-dependent kinase inhibitors now used in breast cancer, including palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio), that prevent cells from entering the cell cycle.5 This leads to cellular senescence. In murine models, aging is associated with dramatic changes in p16INK4a expression in almost all organs over the animals lifespan.6 In human studies, p16INK4a expression is measured in T lymphocytes using a reverse transcription-polymerase chain reaction as a surrogate for aging in other tissues. Studies of p16INK4a expression using other immunohistochemistry methods suggest changes in T cells represent mirror changes in other tissue, and further research in this area is underway.

The change in p16INK4a with aging is not linear, and after 60 years, it appears to plateau for unclear reasons.7 It is possible that those older persons who would have had high levels of p16INK4a expression have already died of age-related illness such as cardiovascular disease, and current studies are addressing this issue.

The large dynamic range of p16INK4a expressionapproximately 10-fold over the human lifespanmakes it an ideal biomarker for study. In healthy children and adolescents, p16INK4a expression is low to undetectable, with high levels appearing in older persons. FIGURE 2 shows the effect of age on p16INK4a expression in 594 patients. These data give p16INK4a expression the potential to be an accurate predictor of cell senescence in an individual patient.

For example, if one hypothesizes that senescent cells are less likely to replicate to ameliorate the adverse effects of chemotherapy (ie, myelosuppression or mucositis), then investigators might be able to accurately predict between 2 patients of the same ageone with high p16INK4a expression and one with lowthat the patient with higher expression would have less cellular reserve and be more vulnerable to adverse effects. Studies are underway to determine if p16INK4a expression measured before treatment will prove to be a predictive marker of toxicity for currently used adjuvant chemotherapy regimens.

Investigators have examined several hundred patients with early breast cancer and a smaller number with childhood cancer and after bone marrow transplantation, and they have found that most chemotherapy regimens cause rapid and sustained increases in p16INK4a expression. Changes are seen shortly and dramatically after beginning chemotherapy, persist over time, and are irreversible.5,8,9 In adolescents and young adults treated with chemotherapy, significant increases in p16INK4a expression were associated with frailty and represented a 35-year acceleration in age among frail young adult cancer survivors. These data mimic what has been clinically noted in large study of adults who had childhood cancer: Approximately one-third of young adults and childhood cancer survivors aged 35 years have a disease phenotype of a person aged 65 years.4 Our group has also found that p16INK4a expression rose markedly in patients treated with allogeneic or autologous stem cell transplants for hematologic malignancies. These patients had a 2- to 3-fold increase in p16INK4a expression corresponding to 16 to 28 years of accelerated aging.10

We have noted similar findings in women with early-stage breast cancer. In patients treated with adjuvant or neoadjuvant chemotherapy, especially with anthracycline-based regimens (doxorubicin, cyclophosphamide, and taxanes with or without carboplatin), p16INK4a expression rose dramatically during chemotherapy and persisted during follow-up. On average, chemotherapy accelerated aging by approximately 17 years of life span, with acceleration of 23 to 27 years for those treated with anthracycline-based treatment.

Of note, docetaxel/cyclophosphamide regimens were associated with only 11 years of aging, and we found no evidence that anti-HER2 therapy affected p16INK4a expression. In these studies, accelerated aging due to chemotherapy represents estimates based on the trajectory of p16INK4a expression in normal patients over their lifespan. We are uncertain of the long-term implications of these changes. In our breast cancer studies, baseline p16INK4a expression was also associated with fatigue. In a recent unpublished analysis (Mitin N, et al), the difference between a patients baseline p16INK4a expression and a normal value for a patient of the same agethe p16 gapwas highly predictive of chemotherapy-induced peripheral neuropathy with taxane chemotherapy. We also found that baseline p16INK4a expression is a significant predictor of a p16 change, independent of age or chemotherapy type, with those patients having lower baseline p16INK4a expression being more likely to have greater changes with any chemotherapy regimen. The reasons for this are unclear, but patients of similar age with higher p16INK4a less ability to overcome tissue and organ damage. Not all chemotherapeutic agentsfor example, taxanes used as a single agentmay be associated with accelerated aging.11 More detailed studies of patients treated with different agents, including immunotherapeutic and other biologic therapies, and for different types of cancer are needed.

The long-term implications of changes in p16INK4a expression with chemotherapy are unknown, but our data suggest that higher levels may be indicators of frailty, a syndrome associate with increased comorbidity, poor quality of life, and shortened survival. p16INK4a expression has been associated with other diseases of aging, including cardiovascular disease, osteoporosis, and other common illnesses, and our chemotherapy-treated patients with accelerated aging may experience major problems 10 to 20 years after treatment, similar to young adults with cancer, and at a time when they are not likely to be followed by their oncologists.

However, these concerns should not mitigate the use of what has proven to be markedly effective treatment regimens that have dramatically improved overall survival in childhood cancer and breast cancer. It is too early to speculate, especially in breast cancer, whether nonanthracycline regimens with similar effectiveness to anthracyclines may be worth considering for patients with long life expectancy. The use of biomarkers in aging research, geroscience, is an exciting area of exploration, and p16INK4a expression is just one of the markers currently being studied.12 The implications of accelerated aging are being studied in other scenarios, and a broad range of studies are exploring interventions to ameliorate biological changes suggesting accelerated aging.

An excellent review of these issues and potential interventions is available13 and describes studies of exercise, diet and nutrition strategies, and senolytics. Learning about the effects of cancer treatment on aging is of major importance, as the clinical scenario of cancer is dominated by older adults who already may have a substantial comorbid illness at the time of diagnosis that might be accelerated by treatment. In children and young adults with cancer, learning how to assess and, in the future, intervene to prevent treatment-related accelerated aging is also a major need.

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Glial Cell Discovery Could Point the Way to Motor Neuron Disease Therapies – Technology Networks

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Scientists at the Francis Crick Institute and UCL have identified the trigger of a key cellular change in amyotrophic lateral sclerosis (ALS), a type of motor neuron disease. The findings could help develop new treatments for many neurological diseases with the same change, including Parkinson's and Alzheimer's.

When the nervous system is injured, diseased or infected, star-shaped cells, called astrocytes, undergo 'reactive' changes in their behaviour. Whilst some of these reactive astrocytes become protective, others become harmful and damage surrounding motor neurons.

Reactive astrocytes are observed in various neurodegenerative diseases including ALS, but there is a lack of understanding about what causes astrocytes to undergo this change.

In their research, published inNucleic Acids Researchtoday (4th March), the scientists compared ALS-diseased astrocytes with healthy astrocytes to uncover how the diseased cells become reactive. These cells were grown from human induced pluripotent stem cells - master stem cells - which can be directed to differentiate into any cell in the human body.

They found that key to the astrocyte change in diseased cells is an increase in the removal of introns (non-coding sections of genetic information) from RNA in a process called splicing. The team identified that in healthy astrocytes there are some RNAs that normally retain certain introns however in diseased cells these particular introns are spliced out.

This has dramatic consequences on the cell's actions as when these introns are cut out of RNA, the remaining exons (coding sections of genetic information) are used as a recipe for building proteins and some of these proteins play a role in the astrocytes changing.

Rickie Patani, senior author, group leader at the Crick, Professor at UCL's Queen Square Institute of Neurology and a consultant neurologist at the National Hospital for Neurology and Neurosurgery, says: "Understanding how astrocytes undergo this transformation is a really exciting step forward. It brings us closer to potentially being able to control and prevent astrocytes from becoming harmfully reactive. While there's still a long way to go, we're hopeful that developing such a treatment is possible and that it could even potentially be used across all neurological conditions in which an increase in reactive astrocytes is also documented, including Parkinson's and Alzheimer's."

ALS is a rapidly progressing degenerative disease. Patients commonly suffer loss of movement, speech and eventually the ability to breathe, and most people only live 3 to 5 years after diagnosis. There are currently no treatments that can meaningfully alter the prognosis.

But understanding key cellular changes associated with ALS could help develop new therapies to slow disease progression.

Oliver Ziff, lead author and clinical fellow at the Crick, UCL's Queen Square Institute of Neurology and a neurology registrar at the National Hospital for Neurology and Neurosurgery, says: "Our group have previously shown that splicing is decreased in ALS motor neurons, so when we found the opposite in ALS astrocytes we were intrigued. In fact, increased splicing is what we find in other immune cells when they become activated or angry. This raises the possibility that ALS astrocytes inflict a toxic immune insult on the nervous system and opens new therapeutic avenues for treating ALS."

The researchers will continue this work to further understand the molecular mechanisms involved when astrocytes become reactive with the ambition of developing an intervention that could be used by doctors to slow disease progression.

Reference: Ziff OJ, Taha DM, Crerar H, et al. Reactive astrocytes in ALS display diminished intron retention. Nucleic Acids Research. 2021;(gkab115). doi:10.1093/nar/gkab115

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Mouth Sores from Chemo: Symptoms, Causes, and Treatments – Healthline

While youre receiving treatment for cancer, some of the drugs you take can cause painful sores to develop inside your mouth. You can also get them if youve had a bone marrow (stem cell) transplant as part of your cancer care.

Although they often heal on their own, these mouth sores can make it uncomfortable to eat and talk. Well discuss what you can do to relieve the pain and prevent them from getting worse.

Mouth sores can be a common side effect of cancer treatment. The condition, known as stomatitis or mucositis, is an inflammation of the tissues inside your mouth.

Whitish, ulcer-like sores can form on your cheeks, gums, lips, tongue, or on the roof or floor of your mouth. Even if you dont develop mouth ulcers, you may have patches that feel inflamed and painful, as if theyve been burned.

Anyone who is receiving chemotherapy, radiation therapy, or a bone marrow (stem cell) transplant can develop mouth sores as a side effect of these treatments.

If you have dry mouth or gum disease, or if your teeth and gums are not well taken care of, you may be at a higher risk of getting mouth sores during your treatment. Women and people who smoke or drink alcohol are also at a higher risk, according to the Oral Cancer Foundation.

If youre receiving chemotherapy, the sores could begin forming anywhere from 5 days to 2 weeks after your treatment. Depending on the specific cause, the sores could go away on their own in a few weeks, or they could last longer.

Its important to find ways to manage your pain and to watch for signs of an infection. Cancer-related mouth sores can lead to weight loss, dehydration, and other serious complications.

Cancer cells can grow very quickly. The aim of cancer treatment is to stop or slow down that growth. The cells in the mucous membranes lining your mouth are also fast-growing cells, so cancer treatments affect them, too.

Cancer treatments also keep the cells in your mouth from being able to repair themselves efficiently when theyre damaged.

Radiation therapy can also damage the glands in your mouth that make saliva. A dry mouth is more susceptible to infections that cause mouth sores.

Chemotherapy and radiation can both change the microbiome in your mouth, upsetting the balance between good and bad bacteria. The growth of harmful bacteria in your mouth can also lead to mouth sores.

Sometimes cancer treatments suppress your immune system, which may make it more likely that youll get a bacterial, viral, or fungal infection that causes mouth sores. An older infection (such as the herpes simplex virus) can also suddenly flare up again.

If youve had a bone marrow (stem cell) transplant, sores may be a sign that youve developed a condition known as graft-versus-host disease (GVHD).

When this happens, the cells in your body are attacking the transplanted cells as though they were an unhealthy invader. According to research published in Journal of Clinical and Experimental Dentistry, short-term (acute) GVHD occurs in 50 to 70 percent of stem cell transplant cases and longer-term (chronic) GVHD is seen in 30 to 50 percent of cases.

The form of GVHD that causes mouth sores is usually mild, and doctors often treat it with corticosteroid medications.

Its important to talk with your doctor if you develop mouth sores after a stem cell transplant, as some kinds of GVHD can turn serious if left untreated.

There is a good chance that youll experience mouth sores at some point during your cancer treatment. Researchers estimate that 20 to 40 percent of those who have chemotherapy and 80 percent of those who have high-dose chemotherapy will develop mucositis afterward.

Still, there are steps you and your cancer care team can take to lower your risk, reduce the severity of the sores, and promote faster healing.

About a month before your cancer treatment begins, schedule an appointment with your dentist to make sure your teeth and gums are healthy. If you have cavities, broken teeth, or gum disease, its important to come up with a dental treatment plan to take care of these conditions so they dont lead to infections later, when your immune system may be vulnerable.

If you wear braces or dentures, ask your dentist to check the fit and remove any part of the device you dont need during your treatment.

Its very important to maintain good oral hygiene practices throughout your treatment to lower your risk of infection. Brush and floss gently but regularly, avoiding any painful areas. You can also ask your dentist whether a mouth rinse with fluoride is advisable in your case.

For certain kinds of chemotherapy (bolus 5fluorouracil chemotherapy and some high-dose therapies), your healthcare team may give you ice chips to chew for 30 minutes before your treatment. This type of cold therapy can lower your risk of getting mouth sores later.

During treatment of some blood cancers, doctors may give you injections of palifermin, also known as human keratinocyte growth factor-1 (KGF-1), to prevent mouth sores.

If youre scheduled to receive high-dose chemotherapy or radiotherapy, your cancer care team may prepare your mouth using low-level laser therapy beforehand to keep you from getting mouth sores.

For people who have radiation therapy for head and neck cancers, doctors may prescribe this medicated mouthwash to minimize mouth sores.

The length of time your mouth sores may last depends on the specific cancer treatment youve had. Here are some estimates broken down by treatment:

You may notice symptoms anywhere between a few days and a few weeks after your cancer treatment. Heres what you may see and feel as mucositis develops:

You may notice that the sores become slightly crusty as they heal. Its important to keep track of your symptoms and let your oncologist know if the sores arent healing on their own.

Contact your doctor right away if you:

Untreated mouth sores can lead to malnutrition, dehydration, and life-threatening infections.

There are a few different ways that you can help mouth sores heal and avoid prolonger pain or an infection.

While the sores are healing, its very important to keep the inside of your mouth clean to prevent an infection from developing.

The National Cancer Institute recommends that you gently clean your teeth every 4 hours and just before you go to sleep at night. Here are a few tips to consider:

If the pain from mouth sores is interfering with your ability to eat and drink, your doctor may treat the condition with a opioid mouthwash or one containing doxepin or lidocaine.

To ease discomfort and keep your mouth from feeling dry, you may want to try rinsing with a mild saltwater or baking soda solution. Heres how to make each of them:

Your cancer care team may recommend that you use a lubricating liquid (artificial saliva) to moisten the inside of your mouth if dryness is a problem. These liquids are usually gel-like. They coat your mouth with a thin film to help ease discomfort and promote healing.

Some people have found it useful to rinse with a blend of medications called the magic mouthwash. Formulas for this mouthwash vary, but most of them include a combination of medications to treat different symptoms, including:

Magic or miracle mouthwash solutions usually have to be prescribed by a doctor and prepared by a pharmacist, although some people mix up an over-the-counter version at home.

There isnt enough research to say for sure whether magic mouthwash works. If you think youd like to try it, talk with your oncologist or a healthcare professional about whether its a good idea for you.

Here are a few more things you can try at home that may help ease pain from mouth sores:

Mouth sores are one of the most common side effects of cancer treatment. Shortly after chemotherapy, radiation, or transplant treatments, painful, ulcer-like sores can form on the inside of your mouth.

These sores may go away on their own. If they dont, its important to seek medical treatment for them because they can lead to very serious complications.

Before you start cancer treatments, visit a dentist to make sure your teeth and gums are healthy. Keeping up good dental hygiene practices during and after cancer treatment will help limit mouth sores.

If the sores are keeping you from eating and drinking, talk with your oncologist about medications could relieve the pain and speed up the healing process, so you can enjoy a better quality of life during treatment.

Its really important to keep track of any sores in your mouth so you can reach out to your healthcare team if they dont improve. Sores that deepen or worsen can lead to serious even life-threatening complications.

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ThermoGenesis Holdings Begins a Year of Celebration of its 35th Anniversary in the Cell Banking and Cell Therapy Industry – PRNewswire

RANCHO CORDOVA, Calif., Feb. 17, 2021 /PRNewswire/ -- ThermoGenesis Holdings, Inc.("ThermoGenesis" or the "Company") (Nasdaq: THMO), a market leader in automated cell processing tools and services in the cell and gene therapy field, announced today that the Company will kick off a year of celebration of its 35th anniversary by aligning its future corporate strategy in offering cell processing systems and services to meet the large-scale cellular manufacturing needs of the increasing number of therapies to be developed over the next decade.

ThermoGenesis has built a solid reputation in the cell banking and cell therapy field. The Company was originally founded in 1986 during a pivotal time, when the stem cell and gene therapy industry was in its infancy. In the early-1990s, ThermoGenesis' original founder, Phil Coelho, formed a long-term collaboration with Dr. Pablo Rubinstein of the New York Blood Center, the father of all cord blood stem cell banking. Together, they invented, patented, and obtained FDA clearance for the first "functionally closed" system for concentrating and isolating stem cells from fresh cord blood samples as well as the protocol for long term cryopreservation of those stem cells to insure retrieval decades later. These breakthrough methods were widely adopted and enabled the cord blood banking industry to grow, expand, and become commercially viable today.

These earliest inventions and protocols were followed by the launch of ThermoGenesis' fully automated BioArchive smart cryopreservation system in 1999 and later its AXP automated cell harvesting system in 2005. These fully automated systems have been adopted by over 130+ leading cord blood transplant centers and other stem cell institutes such as MD Anderson, Cleveland Clinic, Duke University, New York Blood Center in 40+ countries. These systems remain "state-of-the-art" almost 20 years later.

"In the past 20 years, ThermoGenesis and its affiliated companies have helped to advance and shape the landscape of the cell banking industry," said Chris Xu, PhD, Chief Executive Officer of ThermoGenesis. "Cell based therapies have become one of the fastest growing sectors in medicine with over 1,000 clinical trials underway in CAR-T cell therapy alone. As we enter the Company's 35th anniversary, we remain committed to staying as the world's leading technology provider for the cell and gene therapy field."

About ThermoGenesis Holdings, Inc.

ThermoGenesis Holdings, Inc. develops, commercializes, and markets a range of automated technologies for CAR-T and other cell-based therapies. The Company currently markets a full suite of solutions for automated clinical biobanking, point-of-care applications, and automated processing for immuno-oncology, including its semi-automated, functionally-closed CAR-TXpressplatform, which streamlines the manufacturing process for the emerging CAR-T immunotherapy market. For more information about ThermoGenesis, please visit:www.ThermoGenesis.com.

Company Contact:Wendy Samford 916-858-5191 [emailprotected]

Investor Contact:Paula Schwartz,Rx Communications 917-322-2216 [emailprotected]

SOURCE ThermoGenesis Holdings, Inc.

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Meet the women hoping to recruit more stem cells donors from Black communities – CTV News

SASKATOON -- An effort to increase stem cell donors within Black communities across Canada is being driven by a group of women whove had difficulty finding full genetic matches themselves.

Genetic matches are crucial for patients in need of stem cell transplants, such as those with leukemia and lymphoma, and matches are more commonly found within their own racial, ethnic and ancestral groups.

But the new Black Donors Save Lives campaign notes that fewer than two per cent of those in the Canadian Blood Services stem cell donor registry are Black.

And that decreases their chance of finding a match, campaign lead Sylvia Okonofua told CTVNews.ca in a phone interview. It becomes a numbers game for Black people on the stem cell waiting list, where its like finding a needle in a hay stack for them.

The recent University of Regina biochemistry graduate, with sights on becoming a hematologist, timed the virtual campaign to kick off during Black History Month.

It was overall frustrating to know that a patient from my community is so much less likely than other patients to be helped, she told CTVNews.ca. When you see that your people have a really, really low chance of being helped out, it takes you aback.

Okonofua noted part of the campaign uses TikToks, shareable infographics, and even an original song to get the message out and reach a wide audience.

And she said part of the outreach involves having Black stem cell recipients talk about their experiences with the health-care system and speak to the historical mistrust the Black community has towards the medical community.

She founded her campus chapter of Stem Cell Club, a non-profit organization with chapters across Canada which recruits Canadians as potential stem cell donors.

Registration for Black Donors Save Lives can be done online, where participants between the ages of 17 to 35 can fill out a questionnaire and have a swab kit mailed to their address. After they swab the inside of their cheeks and send the sample back, if there is a person in need, 90 per cent of donors will be asked to donate stem cells very similar to the way a person would be giving blood.

But a big difference is the donor is given a growth hormone a week before donation in order to increase the number of stem cells, as well as the process taking four to six hours.

Alternatively, one out of 10 donors will be asked if theyd like to donate stem cells via bone marrow surgery, which can take place over a day.

In 2017, Reve Agyepong experienced firsthand the lack of Black stem cell donors, to treat her sickle cell disease, which involve red blood cells becoming misshapen, which can block blood vessels and lead to damage to bones, brain, kidneys, and lungs, and can ultimately be fatal.

But Agyepong, who was born in Edmonton to Ghanaian parents, was fortunate to receive a stem cell transplant from her sister.

It is such a blessing to have a match within your own family because the percentages are just so low, she told CTVNews.ca by email. I am so fortunate to have found a match in my family or else transplant would have been off the table for me.

In fact, only one in four patients who need a stem cell transplant are able to find a matched donor within their family, with Black patients being less than half as likely as white patients to find a unrelated person they match with on a donor registry, according to the campaign.

For Jamaican-Canadian Dorothy Vernon-Brown, who helped inspire this months campaign, the current efforts are deeply personal. In 2013, she was diagnosed with acute myeloid leukaemia and was heartbroken to discover there were no stem cell matches in Canada's registry or internationally.

She ultimately received stem cells from her sister, who was a half-match, and has been spreading information to Black Canadians ever since, through her own advocacy group, Donor Drive for Dorothy.

Stem cell transplantation is a miracle for patients, and I wish people knew how easy it is to be a stem donor, she recounted on a Twitter thread for another stem cell awareness campaign. You could give someone an opportunity like my sister gave me, to be around and live the life I want. People want to live, so if that gift is in your hands, I appeal to you to see it as something significant to do in your life.

Okonofua and Vernon-Browns efforts are being aided by Dr. Warren Fingrut, a hematologist whos the director of the aforementioned Stem Cell Club.

He told CTVNews.ca in an email hes seen firsthand far too many patients from ethnic and racial minority groups in situations where they dont have fully-matched donors and are forced to seek other treatments.

I find this heart wrenching and I am very motivated to work to address this, Fingrut said.

That led to him founding his non-profit a decade ago, which has gone on to recruit more than 20,000 Canadians as stem cell donors, with more than 55 per cent being non-white. But in cases such as Vernon-Brown and others, those figures need to be much higher.

We started running national campaigns last year, focused on the recruitment of diverse peoples as donors, as well as males who are also preferred by transplant physicians (all else being equal) as they are associated with better outcomes for patients, Fingrut explained.

The campaign is also being done in partnership with several other groups, including the Katelyn Bedard Bone Marrow Association, Black Physicians of Canada, Black Medical Students Association of Canada and the National Black Law Students Association of Canada.

This campaign is one example of an initiative in the health-care sector, which seeks to address racial disparity impacting the care of Black patients, he wrote, noting Black people face many such disparities in access to care, and we want to see others in the health-care sector working with Black Canadians to tackle these issues and address them, in collaboration with Black communities.

Okonofua hopes next Black History Month, theyll be able to have in-person swabbing events in places of worship, community hubs, and cultural gatherings to show how easy it is.

Fingrut said this the first time his group has specifically engaged with one racial group and hopes to expand it to other ethnic and racial communities including South Asians, Indigenous peoples, and those of mixed ancestry in the near future.

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CAR T-Cell Therapy Carves Out a Role in Multiple Myeloma – OncLive

Autologous and allogeneic BCMA-directed CAR T-cell therapies are leading to deep and durable responses in patients with heavily pretreated multiple myeloma, with a low incidence of severe cytokine release syndrome (CRS) and neurotoxicity, explained Yi Lin, MD, PhD, who added that with a pending biologics license application (BLA), the field should start to consider which patients, who dont fit the typical clinical trial eligibility criteria, might be a candidate for the treatment in real-world practice.

On September 22, 2020, the FDA granted a priority review designation to a BLA for idecabtagene vicleucel (ide-cel; bb2121) for the treatment of adult patients with multiple myeloma who have received at least 3 previous therapies, based on data from the pivotal phase 2 KarMMa trial (NCT03361748).

When [these approaches are] available in practice, well have to look at the FDA label, said Lin. Putting that in context with the trial experience and also with what were learning in standard-of-care practice in lymphoma and leukemia, what we will need to understand beyond the approved indication [in a certain] line of therapy is really patient characteristics, such as comorbidities and so on, because we would likely not be restricted by trial criteria anymore. Understanding what a safe condition to use CAR T-cell therapy in while still preserving the efficacy of the product [is something well have to determine].

In an interview withOncLiveduring the 2020 Institutional Perspectives in Cancer webinar on multiple myeloma,Lin, consultant, Division of Hematology, Department of Internal Medicine, consultant, Division of Experimental Pathology and Laboratory Medicine, Department of Laboratory Medicine and Pathology, assistant professor of medicine and oncology, Mayo Clinic, discussed promising data with CAR T-cell therapy in multiple myeloma.

Lin: Cilta-cel [ciltacabtagene autoleucel; JNJ-68284528]and ide-cel are already in pivotal trials. With ide-cel, the BLA has been submitted to the FDA, so were anticipating review in early 2021. Cilta-cel is also getting ready for BLA submission to the FDA as well. Potentially in 2021, we may have these BCMA-targeted CAR T-cell therapies available in standard-of-care practice.

In these trials of heavily pretreated patients with poor-risk cytogenetics and penta-refractory disease, a single infusion of the CAR T [cells is leading to] very high overall response rates. A high percentage of these patients are having deep responses and reaching complete remission [CR] or stringent CR. A good proportion of those patients are also experiencing MRD [minimal residual disease]negative disease. In myeloma, those are relevant metrics in terms of having more durable responses, and were seeing that [thats true with] CAR T-cell therapy as well.

The median PFS [progression-free survival] is around 8.8 months for ide-cel, and the 12-month PFS rate for cilta-cel is close to 77%. Thats very exciting for a patient who has had continuous treatment. We have heard anecdotal reports from these patients on the CAR T-cell therapy trials that when theyre in remission, when theyre recovering post CAR T-cell therapy, its the best they have felt. Its almost like before they had myeloma. Some of these metrics are being formally measured as quality-of-life outcomes in the pivotal trial. Weve seen some of that reported as well in poster format at the 2020 ASH Annual Meeting and Exposition. Those data are very important to consider.

bb21217 is very interesting, because its one of these next-generation approaches were looking at to improve upon CAR T-cell therapy. There are a lot of emerging data regarding the phenotype of CAR T cells in myeloma, including other hematologic malignancies, [in that] the T cell that has more of a nave with memory potential phenotype may contribute to better persistence and more active T cells. Thats one of the ways that bb21217 is trying to approach that.

During manufacturing, theyre exposing the T cells to a PI3K inhibitor to drive the phenotype functions of B cells. Were seeing that with the CAR T cell thats generated from patients on the study, the profiles of the CAR T-cell product do have more presence of these cells [compared with other products]. Its still a little too early to say how the long-term clinical response will look, but initial results, in terms of response rates, are very encouraging.

Thats certainly a possibility. Weve seen the data with ALLO-715; its very early yet. That study only has about 3 months of follow-up, but what weve seen has been very encouraging. The potential advantage of allogeneic CAR T-cell therapy [is that because] youre generating [the allogeneic product] from a healthy donor, the T-cell function or the T-cell health or fitness might be better [than that of an autologous product from a patient with myeloma].

You can also make [the product] ahead of time, so it would be more ready off-the-shelf, but that comes with challenges. You are infusing T cells from somebody else, so there could be a risk for graft-versus-host-disease [GVHD], which we have seen with allogeneic stem cell transplant. This particular product comes with a lot of additional gene editing approaches to try to address that, and so far of about 31 patients who have been dosed, we havent seen any alarming signals for GVHD. These CAR T cells persist and are measurable in patients, which is also very encouraging, and were seeing early signals for response. Were not seeing any concerns yet for the high incidence of more severe CRS, neurotoxicity, or infections.

It will be interesting to see how it is adopted in the market. Ive certainly heard concerns from others in the field that were not quite seeing a plateau in terms of PFS as we have seen in lymphoma. We have to keep in mind that these are very heavily pretreated patients that are studied on trials. I suspect, based on how the trials are designed, that the potential position of where it would be with the final FDA-approved indication would be after 3 lines of prior therapy and exposure to a proteasome inhibitor, IMiD [immunomodulatory drug], and a monoclonal antibody. If it is truly adopted for patients who would be eligible and have access to treatment centers, it could potentially buy them at least a period of time where they dont need any therapies.

Though, we still have patients on these studies that are 2 years out or more in continued remission. I suspect because of how BCMA CAR T-cell therapy worksits really targeting a surface antigen, its not targeting particular cell signaling pathways, and we are seeing responses across other cytogenetic risksthat it wouldnt necessarily impact how well it could function in real-world practice, but thats something that well need to learn as it becomes available.

Its certainly very encouraging to see that, across the CAR T-cell therapy studies, we have not generally seen a very high signal in terms of grade 3 or more severe CRS or neurotoxicity that would require ICU level monitoring. [Such scenarios have] generally [occurred] in single-digit percentages in less than 10% of cases.

There may be some component of how these CARs are designed. There may be some elements of the nature of the myeloma disease that contributes to this, but were also evolving in our understanding of when interventions like tocilizumab (Actemra) and steroids could be safely used to walk that balance between not losing response but preventing more severe toxicities. Within each protocol, the threshold for using tocilizumab and steroids do vary. Generally, there is a move towards using these drugs earlier in the onset of those symptoms, so patients dont have to suffer through the more severe late effects. Theres a variable percentage of patients who get [these interventions], but its a higher percentage than in the earlier studies.

I was most excited to see Allogenes allogeneic product. Whats reassuring is that generally we are seeing response signals, but its a little too early to tell whether that will translate into an advantage in clinical response compared with the current generation CAR T cells. There are lots of products to keep an eye on, but its hard to pick a lead yet.

With the bispecific antibodies, were now seeing some reports from non-BCMA approaches. With a number of BCMA-targeted CAR T-cell therapies and bispecific antibody-drug conjugates, we do need to move into the non-BCMA space fairly quickly. Its very exciting to see pretty high early response rate signals from those approaches as well. CAR T-cell therapies targeting those same antigens are also starting [to be developed], so probably by the 2021 ASH Annual Meeting and Exposition, well hear some results from those studies as well. Immunotherapy approaches are moving very quickly in myeloma, and its always exciting to have those options for our patients.

Its never too early to think about patient selection. Its quite common that patients with myeloma need to get bridging therapy or continue some type of therapy while their autologous CAR T cells are being made. How that may impact or potentially be used to optimize the response of CAR T-cell therapy is not formally studied in a trial. Well learn from real-world practice. In terms of patient access to this product, is there a potentially broader range of conditions and comorbidities where CAR T-cell therapy can still be safely given with a reasonable expectation of response?

GPRC5D and FcRH are the ones that are currently [being developed for] bispecific approaches. CAR T-cell therapy trials will be starting or have recently started [with those targets] as well. Thus far, based on the expression of these targets, they seem to have very limited off-target toxicities. Fingers crossed. Well continue to truly see that profile in the clinical trial settings. Those are the [targets] to really watch out for.

The very first report of CAR T activity in myeloma was with a CD19-directed approach. Theres still some continued effort to see if a combination of CD19 and BCMA have a role in myeloma. To that end, there are some combinations of BCMA-directed CAR T-cell therapy approaches with and CD38 or CS1. Ultimately, the novel targets are the ones to watch out for and likely will have a role, if we do see a desirable response, very quickly after BCMA-directed approaches.

US Food and Drug Administration (FDA) accepts for priority review Bristol Myers Squibb and bluebird bio application for anti-BCMA CAR T cell therapy idecabtagene vicleucel (ide-cel; bb2121). News release. Bristol Myers Squibb and bluebird bio, Inc. September 22, 2020. Accessed February 8, 2021.https://bit.ly/2G0K3Iq.

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CAR T-Cell Therapy Carves Out a Role in Multiple Myeloma - OncLive

AI project to power the future of stem cell manufacturing – TechCentral.ie

Stem cell images from DeepStain project

Valitacell, CeADAR receive 242,000 from Enterprise Ireland and EU

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Read More: AI artifical intelligence CeADAR stem cells Valitacell

A new project to improve stem cell manufacturing using artificial intelligence (AI) could have lasting impacts for the health sector.

The three-year project, entitled DeepStain: Deep Learning for Cell Image Analysis hopes toaccelerate an area of drug development which is at the root of many diseases.

DeepStain is part of a strategic partnership between Irish biotechnology company Valitacell and CeADAR, Irelands Centre for Applied Artificial Intelligence.

The project has received 242,000 funding from Enterprise Ireland and the EU under the Marie Skodowska-Curie Co-Fund Scheme, which is part of the Horizon 2020 Research and Innovation programme.

Stem cells have the potential to treat many conditions including cancer, arthritis, and Crohns disease. Monitoring stem cell quality involves a lot of slow and difficult laboratory work, meaning they can behard to manufacture.

The DeepStain project will use AIto quickly analyse images of stem cells to determine their quality and make stem cell manufacturing more efficient.

The core team is composed of Dr Ricardo Simon Carbajo (CeADAR), Dr Paul Dobson (Valitacell) and Dr PolatGkta(CeADAR & Valitacell), and builds on previous work and interdisciplinary expertise.

AI can massively help to improve the Biopharma value chain, said Dr Ricardo Simon Carbajo, head of innovation & development at CeADAR. In this project, we will be applying the latest techniques in Computer Vision to speed up the process of manufacturing stem cells. We are delighted to partner with Valitacell as they are truly innovating in this area and we can produce a real impact in society.

Working with CeADAR will help Valitacell leverage the power of Deep Learning to create better bioprocess analytical technologies to support stem cell therapy manufacturing, said Dr Paul Dobson, head of data at Valitacell. This will help translate stem cells from being a niche experimental therapy into a treatment available to patients worldwide.

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Read More: AI artifical intelligence CeADAR stem cells Valitacell

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AI project to power the future of stem cell manufacturing - TechCentral.ie

Promising Results for Stem Cell Treatment of Degenerative …

By Pat Anson, PNN Editor

An Australian regenerative medicine company has released positive results from a Phase III randomized trial showing that a single injection of its proprietary stem cell product can provide long-term relief for people with chronic lower back pain caused by degenerative disc disease.

Mesoblast Limited said the results are so promising it plans to meet with the U.S. Food and Drug Administration to discuss ways to accelerate approval of the drug as a treatment that reduces the use of opioid pain medication.

The companys stem cell product -- remestemcel-L -- has been under development for several years. It uses mesenchymal precursor cells taken from the bone marrow of healthy donors to reduce inflammation by inhibiting the production of pro-inflammatory cytokines by white blood cells.

Sixty percent of the patients in the clinical trial who were injected with remestemcel-L reported minimal or no pain after 12 months. After 24 months, 54 percent reported little or no pain, with the greatest pain reduction in patients in the early stages of degenerative disc disease. Many patients also significantly reduced their use of opioids during the study period.

The durable pain reduction for at least two years from a single administration indicates that rexlemestrocel-L has the potential to change the treatment paradigm for chronic low back pain due to inflammatory disc disease, a condition that affects as many as seven million patients across the United States and Europe, and to prevent or reduce opioid use and dependence, Dr. Silviu Itescu, CEO of Mesoblast, said in a statement.

Over 400 patients were enrolled in the Phase III trial, which was conducted at 48 sites around the world, mostly in the United States. Although Mesoblast told physicians and patients not to change any medications during the trial, after 24 months there was a 40% reduction in opioid use in patients injected with rexlemestrocel-L. Those who were given a placebo saline injection increased their daily opioid consumption.

In a previous study of patients with chronic lower back pain who did not respond to conventional treatment, a single injection of remestemcel-L also reduced pain for at least two years.

The FDA has prioritized the development of new pain treatments that reduce the use of opioids. Although the agency has taken a dim view of some stem cell therapies as unproven and potentially dangerous, Mesoblast believes the FDA will be more open-minded about its rexlemestrocel-L treatment. Last year the agency approved an investigational new drug application for rexlemestrocel-L as a therapy for COVID-19.

We now have two studies that show significant pain reduction and were fully prepared to have a discussion with FDA on a path forward, said Mesoblast Chief Medical Officer Dr. Fred Grossman. Were going to get into discussions to see if theres an accelerated path. Or, if we do need to do another study, we now have a very defined patient population where we see significant pain reduction.

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Promising Results for Stem Cell Treatment of Degenerative ...

Stem Cell Therapy for Heart Disease – Cleveland Clinic

Overview Stem Cell Therapy: Helping the Body Heal Itself

Stem cells are natures own transformers. When the body is injured, stem cells travel the scene of the accident. Some come from the bone marrow, a modest number of others, from the heart itself. Additionally, theyre not all the same. There, they may help heal damaged tissue. They do this by secreting local hormones to rescue damaged heart cells and occasionally turning into heart muscle cells themselves. Stem cells do a fairly good job. But they could do better for some reason, the heart stops signaling for heart cells after only a week or so after the damage has occurred, leaving the repair job mostly undone. The partially repaired tissue becomes a burden to the heart, forcing it to work harder and less efficiently, leading to heart failure.

Initial research used a patients own stem cells, derived from the bone marrow, mainly because they were readily available and had worked in animal studies. Careful study revealed only a very modest benefit, so researchers have moved on to evaluate more promising approaches, including:

No matter what you may read, stem cell therapy for damaged hearts has yet to be proven fully safe and beneficial. It is important to know that many patients are not receiving the most current and optimal therapies available for their heart failure. If you have heart failure, and wondering about treatment options, an evaluation or a second opinion at a Center of Excellence can be worthwhile.

Randomized clinical trials evaluating these different approaches typically allow enrollment of only a few patients from each hospital, and hence what may be available at the Cleveland Clinic varies from time to time.

Cleveland Clinic is a large referral center for advanced heart disease and heart failure we offer a wide range of therapies including medications, devices and surgery. Patients will be evaluated for the treatments that best address their condition. Whether patients meet the criteria for stem cell therapy or not, they will be offered the most advanced array of treatment options.

Allogenic: from one person to another (for example: organ transplant)

Autogenic: use of one's own tissue

Myoblasts: immature muscle cells, may be able to change into functioning heart muscle cells

Stem Cells: cells that have the ability to reproduce, generate new cells, and send signals to promote healing

Transgenic: Use of tissue from another species. (for example: some heart valves from porcine or bovine tissue)

Last reviewed by a Cleveland Clinic medical professional on 01/03/2019.

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Stem Cell Therapy for Heart Disease - Cleveland Clinic