Archive for the ‘Bone Marrow Stem Cells’ Category

A student has completed the London Marathon alongside the stem cell donor who saved her life.

icky Lawrence, 21, from Moseley, Birmingham, was diagnosed with severe aplastic anaemia in 2008, when she was eight years old, a condition in which the bone marrow does not produce an adequate number of new blood cells.

Thanks to Elliott Brock, a physiotherapist from Mersea Island, Essex, Ms Lawrence received a transplant that same year.

Ms Lawrence sent Mr Brock a letter in 2015 and the pair met for the first time.

Fast forward to 2021 and they have just completed the London Marathon in support of Anthony Nolan.

Ms Lawrence, who is in her fourth year of a medical degree at Newcastle University, told the PA news agency that completing the marathon was absolutely amazing.

She said: Crossing the finish line was so emotional, not just because wed run 26 miles, but running 26 miles alongside the man who saved your life is a pretty big feat.

Ms Lawrence added: A big slogan of Anthony Nolan is without your support, there is no cure.

Without Elliott donating his stem cells to a stranger, I would not be here. I wouldnt have made it to Christmas. I would never have had the opportunities Ive had to go to university, to study abroad, to play hockey.

Him donating his stem cells gave me a second life and there are still so many people that need a transplant that are not finding the matches they need, especially among the ethnic minority community.

Unfortunately if you are of ethnic minority background, you only have a 37% chance of finding a match.

Mr Brock, 42, who wore a mask and cape during the race, said: That was a tongue of check nod [to the fact that the] easiest way to be called a hero is to donate your bone marrow.

I cannot emphasise to people enough that it is pain-free.

He added: It was just a day of celebration for London to celebrate having their marathon back.

The crowds were amazing and obviously to be side-by-side with the girl whose life, through the amazing work of Anthony Nolan, I managed to save sort of 13 years ago was just surreal really.

Its a lovely story of how my simple act made such a massive difference and we are able to celebrate it so many years after.

Anthony Nolan chief executive Henny Braund said: We are so grateful to Vicky and Elliott for running to raise funds and awareness of Anthony Nolan and the lifesaving work that we do.

Every day five Vickys, patients with blood cancer or a blood disorder, start their search for an Elliott.

If youre aged 16-30 and in good health, please consider joining the Anthony Nolan stem cell register. You could potentially save a life.

More information on how to join the stem cell register can be found at: http://www.anthonynolan.org/help-save-a-life/join-stem-cell-register

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Student completes London Marathon with the man who saved her life - Independent.ie

StemExpress to use utilize the Thermo Fisher Accula rapid PCR testing system to provide event attendees with accurate results in 30 minutes.

Published: Oct. 5, 2021 at 2:33 PM CDT|Updated: 3 hours ago

SACRAMENTO, Calif., Oct. 5, 2021 /PRNewswire/ --StemExpress is proud to announce that they will be the official COVID-19 testing provider for 2021's Meeting on the Mesa, a hybrid event bringing together great minds in the cell and gene biotech sphere. It has partnered with Alliance for Regenerative Medicine to comply with the newly implemented California state COVID-19 vaccination and testing policy regarding gatherings with 1,000 or more attendees. This partnership will allow the vital in-person networking aspect of the event to commence while protecting the health and safety of participants and attendees.

In-person networking commences at the 2021 Cell and Gene Meeting on the Mesa with COVID-19 testing options provided by StemExpress.

As a leading global provider of human biospecimen products, StemExpress understands the incredible impact that Meeting on the Mesa has on the industry and has been a proud participant for many years. For over a decade, StemExpress has provided the cell and gene industry with vital research products and holds valued partnerships with many of this year's participants. As such, it understands the immense value that in-person networking provides and is excited to help bring this element back to the meeting safely and responsibly.

StemExpress has been a trusted provider of widescale COVID-19 testing solutions since early 2020 - providing testing for government agencies, public health departments, private sector organizations, and the public nationwide. For Meeting on the Mesa, StemExpress is offering convenient testing options for unvaccinated attendees and those traveling from outside of the country. Options will include take-home RT-PCR COVID Self-Testing Kits and on-site, rapid PCR testing for the duration of the event. The self-testing kit option allows attendees to test for COVID in the days leading up to the event for a seamless admission and the days following the event to confirm they haven't been exposed. The on-site rapid testing option utilizes the new Thermo Fisher Accula, offering in-person testing at the event with results in around 30 minutes. StemExpress is excited to bring these state-of-the-art COVID testing solutions to the frontlines of the Cell & Gene industry to allow for safe in-person connections.

The StemExpress partnership with Alliance for Regenerative Medicine seeks to empower the entire cell and gene industry with a long-awaited opportunity to return to traditional networking practices. It is well known that innovation doesn't exist in a vacuum - allowing great minds to come together is a sure way to spur scientific growth and advance cutting-edge research, giving hope for future cures.

Cell and Gene Meeting on the Mesa will take place October 12th, 2021, through October 14th, 2021, at Park Hyatt Aviara,7100 Aviara Resort Drive Carlsbad, CA 92011. To learn more about the event, please visit MeetingOnTheMesa.com.

For more information about COVID testing solutions for businesses and events, visit https://www.stemexpress.com/covid-19-testing/.

About StemExpress:

Founded in 2010 and headquartered in Sacramento, California, StemExpress is a leading global biospecimen provider of human primary cells, stem cells, bone marrow, cord blood, peripheral blood, and disease-state products. Its products are used for research and development, clinical trials, and commercial production of cell and gene therapies by academic, biotech, diagnostic, pharmaceutical, and contract research organizations (CRO's).

StemExpress has over a dozen global distribution partners and seven (7) brick-and-mortar cellular clinics in the United States, outfitted with GMP certified laboratories. StemExpress runs its own non-profit supporting STEM initiatives, college and high school internships, and women-led organizations. It is registered with the U.S. Food and Drug Administration (FDA) and is continuously expanding its network of healthcare partnerships, which currently includes over 50 hospitals in Europe and 3 US healthcare systems - encompassing 31 hospitals, 35 outpatient facilities, and over 200 individual practices and clinics.

StemExpress has been ranked by Inc. 500 as one of the fastest-growing companies in the U.S.

About the Alliance for Regenerative Medicine:

The Alliance for Regenerative Medicine (ARM) is the leading international advocacy organization dedicated to realizing the promise of regenerative medicines and advanced therapies. ARM promotes legislative, regulatory, reimbursement and manufacturing initiatives to advance this innovative and transformative sector, which includes cell therapies, gene therapies and tissue-based therapies. Early products to market have demonstrated profound, durable and potentially curative benefits that are already helping thousands of patients worldwide, many of whom have no other viable treatment options. Hundreds of additional product candidates contribute to a robust pipeline of potentially life-changing regenerative medicines and advanced therapies. In its 12-year history, ARM has become the voice of the sector, representing the interests of 400+ members worldwide, including small and large companies, academic research institutions, major medical centers and patient groups. To learn more about ARM or to become a member, visit http://www.alliancerm.org.

Media Contact: Anthony Tucker, atucker@stemexpress.com

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StemExpress Partners with the Alliance for Regenerative Medicine to Provide COVID-19 Testing for the Cell and Gene Meeting on the Mesa - WSAW

Published: Oct. 4, 2021 at 6:00 AM EDT

NEW YORK, Oct. 4, 2021 /PRNewswire/ -- BrainStorm Cell Therapeutics Inc. (NASDAQ: BCLI), a leading developer of cellular therapies for neurodegenerative diseases, announced today that Stacy Lindborg, Ph.D., Executive Vice President and Head of Global Clinical Research, will deliver a presentation at the2021 Cell & Gene Meeting on the Mesa, being held as a hybrid conferenceOctober 12-14, and October 19-20, 2021.

Dr. Lindborg's presentation highlights the expansion of Brainstorm's technology portfolio to include autologous and allogeneic product candidates, covering multiple neurological diseases. The most progressed clinical development program, which includes a completed phase 3 trial of NurOwn in ALS patients, remains the highest priority for Brainstorm. Brainstorm is committed to pursuing the best and most expeditious path forward to enable patients to access NurOwn.

Dr. Lindborg's presentation will be in the form of an on-demand webinar that will be available beginning October 12. Those who wish to listen to the presentation are required to registerhere. At the conclusion of the 2021 Cell & Gene Meeting on the Mesa, a copy of the presentation will also be available in the "Investors and Media" section of the BrainStorm website underEvents and Presentations.

About the 2021 Cell & Gene Meeting on the Mesa

The meeting will feature sessions and workshops covering a mix of commercialization topics related to the cell and gene therapy sector including the latest updates on market access and reimbursement schemes, international regulation harmonization, manufacturing and CMC challenges, investment opportunities for the sector, among others. There will be over 135 presentations by leading public and private companies, highlighting technical and clinical achievements over the past 12 months in the areas of cell therapy, gene therapy, gene editing, tissue engineering and broader regenerative medicine technologies.

The conference will be delivered in a hybrid format to allow for an in-person experience as well as a virtual participation option. The in-person conference will take place October 12-14 in Carlsbad, CA. Virtual registrants will have access to all content via livestream during program dates. Additionally, all content will be available on-demand within 24 hours of the live program time. Virtual partnering meetings will take place October 19-20 via Zoom.

About NurOwn

The NurOwntechnology platform (autologous MSC-NTF cells) represents a promising investigational therapeutic approach to targeting disease pathways important in neurodegenerative disorders. MSC-NTF cells are produced from autologous, bone marrow-derived mesenchymal stem cells (MSCs) that have been expanded and differentiated ex vivo. MSCs are converted into MSC-NTF cells by growing them under patented conditions that induce the cells to secrete high levels of neurotrophic factors (NTFs). Autologous MSC-NTF cells are designed to effectively deliver multiple NTFs and immunomodulatory cytokines directly to the site of damage to elicit a desired biological effect and ultimately slow or stabilize disease progression.

About BrainStorm Cell Therapeutics Inc.

BrainStorm Cell Therapeutics Inc. is a leading developer of innovative autologous adult stem cell therapeutics for debilitating neurodegenerative diseases. The Company holds the rights to clinical development and commercialization of the NurOwntechnology platform used to produce autologous MSC-NTF cells through an exclusive, worldwide licensing agreement. Autologous MSC-NTF cells have received Orphan Drug designation status from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of amyotrophic lateral sclerosis (ALS). BrainStorm has completed a Phase 3 pivotal trial in ALS (NCT03280056); this trial investigated the safety and efficacy of repeat-administration of autologous MSC-NTF cells and was supported by a grant from the California Institute for Regenerative Medicine (CIRM CLIN2-0989). BrainStorm completed under an investigational new drug application a Phase 2 open-label multicenter trial (NCT03799718) of autologous MSC-NTF cells in progressive multiple sclerosis (MS) and was supported by a grant from the National MS Society (NMSS).

For more information, visit the company's website atwww.brainstorm-cell.com.

Safe-Harbor Statement

Statements in this announcement other than historical data and information, including statements regarding future NurOwnmanufacturing and clinical development plans, constitute "forward-looking statements" and involve risks and uncertainties that could cause BrainStorm Cell Therapeutics Inc.'s actual results to differ materially from those stated or implied by such forward-looking statements. Terms and phrases such as "may," "should," "would," "could," "will," "expect,""likely," "believe," "plan," "estimate," "predict," "potential," and similar terms and phrases are intended to identify these forward-looking statements. The potential risks and uncertainties include, without limitation, BrainStorm's need to raise additional capital, BrainStorm's ability to continue as a going concern, the prospects for regulatory approval of BrainStorm's NurOwntreatment candidate, the initiation, completion, and success of BrainStorm's product development programs and research, regulatory and personnel issues, development of a global market for our services, the ability to secure and maintain research institutions to conduct our clinical trials, the ability to generate significant revenue, the ability of BrainStorm's NurOwntreatment candidate to achieve broad acceptance as a treatment option for ALS or other neurodegenerative diseases, BrainStorm's ability to manufacture, or to use third parties to manufacture, and commercialize the NurOwntreatment candidate, obtaining patents that provide meaningful protection, competition and market developments, BrainStorm's ability to protect our intellectual property from infringement by third parties, heath reform legislation, demand for our services, currency exchange rates and product liability claims and litigation; and other factors detailed in BrainStorm's annual report on Form 10-K and quarterly reports on Form 10-Q available athttp://www.sec.gov. These factors should be considered carefully, and readers should not place undue reliance on BrainStorm's forward-looking statements. The forward-looking statements contained in this press release are based on the beliefs, expectations and opinions of management as of the date of this press release. We do not assume any obligation to update forward-looking statements to reflect actual results or assumptions if circumstances or management's beliefs, expectations or opinions should change, unless otherwise required by law. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee future results, levels of activity, performance or achievements.

ContactsInvestor Relations:Eric GoldsteinLifeSci Advisors, LLCPhone: +1 646.791.9729egoldstein@lifesciadvisors.com

Media:Paul TyahlaSmithSolvePhone: + 1.973.713.3768Paul.tyahla@smithsolve.com

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SOURCE Brainstorm Cell Therapeutics Inc

The above press release was provided courtesy of PRNewswire. The views, opinions and statements in the press release are not endorsed by Gray Media Group nor do they necessarily state or reflect those of Gray Media Group, Inc.

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BrainStorm to Present at the 2021 Cell & Gene Meeting on the Mesa - WWNY

July13, 20216 min read

Opinions expressed by Entrepreneur contributors are their own.

On June 13, Laura Wilkinson did not qualify in her attempt to join this years U.S. Olympic Diving Team finishing inonly 10th place at the final qualifying event in Indianapolis.

But Lauras performance was so inspiring that she received a standing ovation from everyone who attended. Why? Because at age 43, Laura is now more than twice as old as she was when she won her gold medal at the 2000 Olympics in Sydney.

While it may not be surprising that she didnt qualify for this years team, the very idea that she was in shape to compete at all clearly shows how much progress weve made in not only extending longevity, but also living healthier as we age. In the last century alone, average life expectancy in the U.S. has increased from around 60 to nearly 80 years.

At this rate, it wont be long before 100 years old becomes "the new 60."

Indeed, new scientific discoveries and innovative research into health and medicine continueto reveal new insights into how the human body works and how we can delay the impact of aging many that we couldnt even imagine only a few short years ago.

Related:Former Quarterback Jim McMahon Calls AdvancedStem-Cell Therapy 'Truly Miraculous'

As the CEO of BioXcellerator, a leading stem-cell treatment and research center, Ive made it my mission to work with a team of talented scientists and physicians to further progress to help everyone worldwide live longer and enjoy better health.

Weve long known about the benefits of a healthy lifestyle and diet. And physicians now have access to more advanced surgical procedures and new medications. But as it turns out, the secret to maintaining excellent health and vitality isnt so secretive at least at the cellular level.

You see, your body already knows how to heal itself, through a natural process based on stem cells. Youre not aware of it, of course, but all of the cells in your body neurons in your brain, cardiac cells in your heart, immune cells that circulate through your bloodand all other cells are constantly being replaced with new cells.

Yet even though each type of cell functions differently, they all begin as stem cells created in your bone marrow, then differentiated to become a specific type of cell.

As we age, however, stem-cell production declines. Thats why stem-cell therapy is such an exciting frontier in medicine today:After an infusion of millions of high-potency stem cells, your body goes right to workusingthose cells to heal damaged tissue, reduce inflammation, improve immunity, and boost vitality and performance.

Even damage from injuries sustained many years ago can be healed from an infusion of stem cells.

Related:This Is HowStem-CellTherapy Treats Serious Brain Injuries

Although more effective medical treatments for various diseases and disorders certainly benefits humanity, heres a better approach: Prevent disease in the first place. Yes, nutrition and exercise make a big difference, but recent studies clearly show how enhancing immunity and reducing chronic inflammation can add even more years to our lives and improve our health.

Yet, while were aware of what we eat and our level of physical activity, we dont fully appreciate the battle our immune cells fight every minute of every day 24/7. Theyre constantly on patrol throughout your body, seeking out and destroying various viruses and other microbes that threaten our health and lives. That may seem overly dramatic, but one things for sure:Without immunity, there would be no humanity. Our species couldnt exist.

Another battle that rages inside us comes in the form of inflammation. Although inflammation is the bodys natural signaling system that various tissues need repair and healing, when continued ongoing inflammation becomes chronic, it can actually cause even more serious damage throughout the entire body. Recent studies suggest that while an anti-inflammatory diet and other lifestyle choices (for example, getting enough sleep) can reduce excess inflammation, stem cells also provide anti-inflammatory benefits and boost immunity too.

At BioXcellerator, we offer stem-cell therapy to treat a wide range of diseases and injuries, but regardless of what patients get treated for, one common resultrings loud and clear:Patients report that they feel better. They have more vitality, moreenergy, enhanced cognitive function and a greater overall sense of well-being.

After all, the body doesnt know why its receiving new stem cells, so it uses those cells to both heal specific damage and better modulate the immune system and regulate inflammation.

Related:High-Potency 'GoldenCells' Offer Hope to Those With Severe Brain Injuries

With even more advanced testing now available, such as whole-body and brain MRIs, genome sequencing andliquid biopsy using cell-free DNA, we can detect the onset of many serious diseases and disorders far earlier, including heart disease, cancer, and autoimmune and degenerative conditions.

Theres overwhelming evidence that many cancers and heart disease can be treated more effectively when detected at an early stage. These more accurate and precise tests also enable us to provide personalized recommendations forchanges in diet and lifestyle that can help prevent or delay the onset of many diseases and conditions altogether.

Many athletes turn to stem cells to maintain peak performance duringtheir careers, and to extend them;they also receive treatment after they retire to alleviate chronic pain from injuries suffered over many years.

No, its not so miraculous. Its all based on science. As we learn more about extending longevity, immunityand performance, Im more convinced than ever that age 100 will become the new 60.

Excerpt from:
The Future of Health: Why Age 100 Will Soon Become 'the New 60' - Entrepreneur

Introduction

Profilin 1 (PFN1) is a ubiquitous small-molecule protein that exists in all eukaryotes.1 PFN1 was first identified as a G-actin sequestering molecule,2 and subsequently, its true functions in actin polymerization and F-actin dynamics were revealed.3 In the following decades, the structure of PFN1 was recognized to have 3 domains: an actin-binding domain,4 a poly-L-proline (PLP)-binding domain,5 and a phosphoinositide-binding domain.6

PFN1 plays a vital role in many cell functions, including membrane trafficking, endocytosis, cell cycle, motility, proliferation, cell survival, transcription, stemness, and autophagy (Figure 1). Abnormal expression or deletion of PFN1 can affect the normal physiological activity of cells and lead to disease development. PFN1 has been deeply studied in a variety of diseases, some genetic (eg, amyotrophic lateral sclerosis)7 and some chronic (eg, hypertension).8

In the past 10 years, PFN1s role in cancer has received increasing attention. In this review, we summarize the studies of PFN1 in cancer that have been completed in recent years, discuss the roles of PFN1 in cancer, and discuss the implications for tumor diagnosis and therapy in the future.

Early diagnosis of cancers is still a major challenge worldwide, and early detection can notably reduce their associated morbidity and mortality.9 PFN1, a critical actin-binding protein, is found to be dysregulated in many cancers, which makes it possible to use it as a biomarker for diagnosis and prognosis. PFN1 mainly plays a role in the cytoplasm, but it can also be found in the nucleus and can even be secreted into the extracellular space. The rich knowledge in the proteomics field makes the detection of proteins for new diagnostic markers and targets for therapy possible.10

In some tumor types (such as renal cell carcinoma [RCC], gastric cancer, and others), high expression of PFN1 indicates later stage and worse prognosis. Via differential proteomics, PFN1 has been identified in metastatic and primary RCC, and further analysis indicated that high PFN1 expression was associated with poor outcome and that PFN1 could be used as a potential prognostic marker in RCC.11 In clear-cell RCC (ccRCC), the expression of PFN1 was decreased in early-stage tumors compared with normal tissues. However, its expression in stage IV ccRCC was significantly increased. PFN1 was selected as a candidate marker of late-stage ccRCC.12 Results of a recent study determined that the vast majority of ccRCC tumors tend to be selectively PFN1-positive in stromal cells only; dramatic transcriptional upregulation of PFN1 was found in tumor-associated vascular endothelial cells in clinical specimens of ccRCC.13 Tissue microarray results also showed that PFN1 was increased in metastatic ccRCC compared with primary tumors. Univariate analysis suggested that higher PFN1 expression was associated with shorter disease-free survival (HR, 7.36; P = .047) and lower overall survival.14

In gastric cancer, Tanaka et al found that PFN1 was highly expressed in fetal rat stomach. Additionally, PFN1 was overexpressed in some human and rat gastric cancers.15 The results of later studies indicated that PFN1 expression was higher in gastric cancer tissues than in adjacent normal tissues. High PFN1 expression was correlated with tumor infiltration, lymph node metastasis, and tumor-node-metastases (TNM) stage. Functional assays confirmed that silencing PFN1 could inhibit the invasion and migration of gastric cancer cell lines.16

In addition, PFN1 expression was higher in nonsmall cell lung cancer (NSCLC). Lower expression of PFN1 was associated with better prognosis and a higher survival rate in NSCLC.17 Proteomic analysis revealed that PFN1 was differentially expressed in laryngeal carcinoma tissues compared with adjacent normal tissues. Further study results revealed that PFN1 was increased in laryngeal carcinoma tissues compared with adjacent normal tissues, indicating that PFN1 was a novel potential biomarker for the diagnosis of laryngeal carcinoma.18

However, in some other tumors (such as colorectal cancer [CRC], oral carcinoma, and others), the opposite is true. PFN1 was downregulated in pancreatic cancer.19-20 Lower expression of PFN1 was significantly associated with a shorter survival period.20 In late-stage oral squamous cell carcinoma, PFN1 expression was lower than that in normal oral epithelium, and loss of PFN1 expression was related to invasion into and metastasis of lymph nodes.21 PFN1 was also decreased in late advanced hepatocellular carcinoma (HCC) and was associated with a poor survival rate of patients.22-23 In addition, PFN1 was found to be downregulated in nasopharyngeal carcinoma24 and breast cancer.25 Combined with another 4 actin-binding proteins, PFN1 could be used to construct a model for predicting poor prognosis of esophageal squamous cell carcinoma.26

Under normal physiological conditions, PFN1 is involved in multiple cellular functions, such as cell motility, migration, adhesion, and transduction signaling pathways.27 PFN1 is differentially expressed in various types of tissues and cells, which may explain its variable tumorigenic mechanisms in different tumors, even in different stages of the same cancer (Figure 2). Because PFN1 plays important roles in tumorigenesis and progression, targeting PFN1 dysregulation could to some extent influence the prognosis of patients with cancer. Determining the expression of PFN1 could thus be used to distinguish high-risk disease from lower-risk disease. Combination with other indices could further improve the diagnostic and prognostic value of PFN1.

In addition to dysregulation in tumor tissues, PFN1 was also found to bedifferentially expressed in the serum, urine, and extracellular vesicles of patients with cancer, which makes it possible to utilize PFN1 in liquid biopsy analysis of tumors. Compared with tumor tissue biopsy, liquid biopsy is a more practical method for real-time monitoring of patients with cancer.28 In addition, PFN1 was detected in the supernatants of cultured cells.

It has been shown that PFN1 gene expression is increased in peripheral blood cells of patients with HCC compared with healthy controls.29 A 9-gene expression system (including PFN1) was used to discriminate patients with HCC from healthy people.30 Proteomic analysis of serum proteins showed that PFN1 was increased in patients with gallbladder cancer. The expression difference between these patients and healthy controls was more than 2-fold.31 PFN1 was differentially expressed in the urine of patients with invasive and noninvasive bladder cancer. Further studies confirmed that PFN1 was notably decreased in the epithelium of invasive bladder tumors compared with noninvasive tumors, which was associated with the clinical outcomes of bladder cancer.32 In in vitro pancreatic cancer cell lines, PFN1 was downregulated in secretomes compared with nonneoplastic pancreatic ductal cells.33 In invitro cultured RCC cell lines, PFN1 was differentially regulated in the supernatant. Further studies revealed that PFN1 was upregulated in RCC tissues.34 Apart from its dysregulation in serum and urine, PFN1 was found to be downregulated in the circulating leukocytes of patients with breast cancer compared with healthy controls, which provides a new paradigm for highly sensitive and less invasive approaches for the diagnosis of breast cancer.35 Studies have already revealed that PFN1 can be secreted via exosomes or other secretory pathways.36-38

Extracellular PFN1 in the tumor microenvironment can be taken up by recipient cells and execute its function in recipient cells, which in turn may influence the biological behavior of cells in the microenvironment, ultimately affecting tumorigenesis and progression of cancers. As mentioned above, PFN1 is expressed differentially in the serum and urine of patients with cancer, which enables its application as a biomarker for diagnosis and prognosis in liquid biopsy (Table 1).

Cell motility involves membrane protrusion, cell matrix adhesion, cell body translocation, and rear detachment. Many of these processes require the actin cytoskeleton and its regulators. By facilitating the exchange of ATP for ADP on G-actin, PFN1 plays a major role in actin polymerization, thus influencing motility in numerous cells.39 PFN1 also participates in cell motility by regulating actin polymerization and interactions with other regulators of actin cytoskeletons, such as ARP3, VASP, and proteins of cell signaling pathways. Cell-cell adhesion and cell-matrix adhesion are critical contributors to maintaining tissue architecture. Dysregulation of cell-cell adhesion is an important sign in tumor initiation and progression of malignancy. PFN1 can modulate cell adhesion and epithelial-to-mesenchymal transition (EMT) in cancer cells. However, the mechanisms by which PFN1 regulates cell adhesion are still not very clear. Undoubtedly, learning more about the roles of PFN1 in cell adhesion and motility will help us better understand its roles in modulating tumor invasion and migration.

Since PFN1 plays a critical role in actin polymerization, it is an indispensable regulator of cell motility. PFN1 participates in the invasion and metastasis of multiple cancers. However, the roles of PFN1 in regulating cell motility are context specific.27 Exogenous PFN1 with intact actin-binding abilities can ameliorate the adherence and spreading capabilities of cancer cells and exert tumor-suppressive effects in breast cancer.40 Consistent with the results of the study by Wittenmayer et al, Zou et al found that PFN1 overexpression could revert MDA MB-231 cells to an epithelioid phenotype, with restored adherence junctions.41 In addition, PFN1 overexpression could promote AMPK activation and p27 phosphorylation, which in turn induces epithelial morphological reversion of mesenchymal breast cancer through restoration of adherens junctions.42 These studies highlighted the involvement of PFN1 in epithelial adhesion and differentiation, which helped us better understand its roles in cancer cell motility.

Invadopodia are actin-driven membrane protrusions that can deliver matrix metalloproteinases to degrade the matrix and support invasion and dissemination of tumor cells. Any dysregulation of the actin cytoskeleton can impair the formation and maturation of invadopodia.43-46 PFN1 can regulate PI(3,4)P2, which in turn negatively regulates lamellipodin at the leading edge of breast cancer cells and thus inhibits those cells motility.47 The depletion of PFN1 leads to an increase in the level of PI(3,4)P2 in invadopodia and its interacting adaptor Tks5. The interaction of PI(3,4)P2-Tks5 has been shown to promote the anchorage, maturation, and turnover of invadopodia, which in turn enhances the invasiveness and motility of breast cancer.48 Breast cancer is an invasive adenocarcinoma, and numerous studies have found that PFN1 is downregulated in breast cancer tissues.49-54 Overexpression of PFN1 reduces the invasion and migration of breast cancer cells, while loss of PFN1 significantly enhances breast cancer cell motility and invasion. Mechanisms involved in PFN1s negative roles in breast cancer metastasis include Enabled (Ena)/vasodilator stimulated phosphoprotein (VASP)-dependent lamellipodial protrusion,51 miRNA-182 regulation,52 and regulation of PFN1 degradation.53 Mouneimne et al found that PFN1 knockdown (KD) could increase F-actin bundles and enhance stress fiber formation. In that study, the numbers of protrusions in PFN1-KD cells were markedly decreased, and PFN1-KD could inhibit the motility of breast cancer.55 Moreover, Liu et al indicated that the interaction of LMO2-PFN1 and LMO2-ARP3 could promote the formation of lamellipodia/filopodia in basal-type breast cancer cells.56 Ena/VASP is a critical regulator of the actin cytoskeleton at the leading edge of cells, which controls membrane protrusions and cell motility. Cell-substrate adhesion and downregulation of Protein Kinase A (PKA) promote interactions of PFN1 with VASP, which is another mechanism by which PFN1 regulates cell motility.57-58 Knockdown of PFN-1 has been shown to abrogate the inhibitory effect of tyrphostin A9, suggesting that modulating PFN1 expression could have therapeutic potential in the treatment of metastatic breast cancer.59

As in breast cancer, PFN1 was found to be a suppressor of migration in HCC.22,23,60 All-trans retinoic acid60 and guttiferone K22 could inhibit hepatocellular cell migration and proliferation by upregulating the expression of PFN1. In prostate cancer, cathepsin X can inactivate PFN1, thus promoting adhesion, invasion, and migration of cancer cells.61 In CRC, elevated expression of PFN1 obviously inhibited invasion and migration. PFN1 was suppressed by the HLA-F-AS1/miRNA-330-3p/PFN1 or HCP5/miRNA-299-3p/PFN1/AKT axis.62-63

Interestingly, Ding et al showed that in the early stages of metastasis, breast cancer cells exhibit a hyperinvasive phenotype characterized by upregulation of MMP-9 and by faster invasion when PFN1 expression is downregulated. However, in the late stages of metastasis, loss of PFN1 markedly inhibits the growth of metastatic colonies of breast cancer cells.54 Rizwani et al reported that PFN1 expression was elevated in breast cancer tissues and that overexpression of PFN1 could inhibit the migration of breast cancer cells. The phosphorylation of S137 mutants abrogated PFN1s promotion of migration. These studies provided a different vision of PFN1s role in breast cancer metastasis.64

In gastric cancer, silencing PFN1 inhibited the invasion and migration of cells, and the PFN1 expression level in cancer tissue was positively correlated with tumor infiltration and lymph node metastasis.16 However, different conclusions were drawn from the study of Ma et al. The authors found that PFN1 expression was inversely correlated with lymph node metastasis.65 In the lung cancer cell line A549, downregulation of PFN1 inhibited migration.17 In addition, in vitro studies support the importance of PFN1 in the proliferation and migration of RCC cells, and treatment with a novel computationally designed PFN1-actin interaction inhibitor reduced the proliferation and migration of RCC cells in vitro and RCC tumor growth in vivo.13 Additional studies have demonstrated that downregulation of PFN1 can also suppress the migration of laryngeal cancer18 and bladder cancer.66

Although more studies on PFN1 have been completed recently, its roles in cancer metastasis are still unclear. The concentrations of actin and PFN1 are time- and space-specific, and so is the regulation of the actin cytoskeleton (Table 2). Additional thorough studies are needed to comprehend the mechanisms and laws regulating the actin cytoskeleton. More importantly, in addition to actin dependence, PFN1 affects cell migration in an actin-independent manner by interacting with proteins with PIP2 or PLP domains. Furthermore, lncRNAs and microRNAs also modulate the functions of PFN1. All of these proteins and RNAs interact with PFN1 and indirectly influence the functions of cancer cells, which makes understanding the roles of PFN1 in cancer metastasis and other functions more complicated (Table 3).

In yeast, the gene encoding PFN1 is essential for cytokinesis.67 Early studies revealed that PFN1/ embryos died as early as the 2-cell stage, while PFN1/+ embryos displayed reduced survival during embryogenesis compared with wild-type embryos; this indicates that PFN1 is essential for cell division and survival during embryogenesis.68 PFN1 silencing in endothelial cells inhibits proliferation.69 In addition, homozygous deletion of PFN1 in chondrocytes failed to complete abscission at late-stage cytokinesis.70 The results of all these studies imply that PFN1 plays a role in cell proliferation. In breast cancer, PFN1 overexpression (PFN1-OE) has been shown to inhibit cell growth and exert an inhibitory effect on tumorigenesis,25,40,52,71-75 and PFN1-OE suppresses the activation of AKT, which in turn inhibits the growth of tumor cells.71 PFN1-OE cells arrested at the G1 phase, which was partly attributed to the upregulation of P27kip1.72 miRNA-182 could downregulate PFN1 expression and promote triple-negative breast cancer cell proliferation.52 However, Yap et al put forward opposite views. The authors research results revealed that silencing PFN1 resulted in a multinucleation phenotype of breast cancer cells, thus inhibiting proliferation.76 Recent studies from Chakraborty et al also reported that PFN1 knockdown could upregulate SMAD3 and inhibit the proliferation of breast cancer.77 Results of single-cell studies on the extracellular matrix revealed that stiff extracellular matrix led to upregulation of PFN1, possibly promoting the proliferation of breast cancer.78 Apart from breast cancer, PFN1 was also found to suppress proliferation in pancreatic adenocarcinoma,20 endometrial cancer,79 and HCC.23,60 In gastric cancer, silencing PFN1 caused cell cycle arrest at G0/G1 phase, thus restraining cell proliferation.16 Knockdown of PFN1 could also inhibit the proliferation of laryngeal cancer.18 Our previous studies found that overexpression of PFN1 could promote the proliferation of multiple myeloma cells by accelerating the cell cycle from G1 to S phase.80 PFN1 is indispensable for cytokinesis. Nevertheless, PFN1 is involved in regulating cell proliferation not only by impacting cytokinesis but also by modulating cell cyclerelated proteins. Otherwise, PFN1 could also interact with cell signaling pathways and indirectly influence cell proliferation.

Tumor growth is not only about uncontrolled proliferation but also resistance to apoptosis.81 Actin dynamics have notable impacts on multiple stages of apoptosis.82 PFN1, as a critical actin-binding protein, is an indispensable regulator of actin dynamics, through which PFN1 participates in regulating apoptosis. PFN1 overexpression could upregulate the most common tumor-associated hotspot mutation of p53p53R273Hthus sensitizing cancer cells to apoptosis via the intrinsic apoptotic pathway.83 PFN1 has been shown to facilitate apoptosis of breast cancer cells, thus exerting a suppressive effect on tumorigenesis.73,75,83,84 By inducing apoptosis and reducing autophagy, PFN1 has also been shown to sensitize pancreatic cancer cells to irradiation. Additionally, overexpression of PFN1 can significantly elevate apoptotic markers such as cleaved caspase-3 and cleaved PARP after irradiation, suggesting that PFN1 can modulate radiosensitivity partly by regulating apoptosis.85

Given that PFN1 is involved in cell proliferation and apoptosis, it is not difficult to understand its roles in the drug resistance of tumor cells. PFN1 was found to be downregulated in butyrate-treated CRC cells,86 and proteomics studies revealed that PFN1 was differentially expressed in erinacine Atreated CRC cells,87 which suggested the roles of PFN1 in drug-mediated cell death and inhibition of proliferation. In addition, proteomics showed that PFN1 was differentially expressed in mitotane-treated adrenocortical carcinoma,88 and PFN1 was found to be increased in tocotrienol-treated MDA-MB-231 cells,89 indicating its roles in predicting the response to anticancer therapies. Compared with temozolomide (TMZ)-treated glioblastoma cells, PFN1 was downregulated in OKN-007 combined with TMZ-treated glioblastoma cells. Further study results revealed that PFN1 is involved in TMZ resistance.90 Results of our previous studies showed that PFN1 could interact with the Beclin 1 complex and participate in bortezomib resistance in multiple myeloma.80 Since PFN1 is involved in multiple cell processes, including proliferation, apoptosis, and proteomics, it was recognized as a biomarker for therapy sensitivity, and it is worth further exploring its roles in drug resistance. In addition, PFN1 was found to participate in angiogenesis,91-92 initiation of tumors,93 and autophagy.80 Loss of PFN1 in A549 cell lines resulted in fewer early apoptotic cells after treatment with piperlongumine, and PFN1 sensitized A549 cells to anticancer agents.17 PFN1 serves as a bridge for actin-cytoskeleton and cell signaling pathways and is involved in multiple biological and physiological processes. Dysregulation of PFN1 in cancer cells has a notable impact on sensitivity to chemotherapy or radiotherapy and may be a new target for the treatment of drug-resistant or radioresistant patients.

Studies have already confirmed that PFN1 is essential for cell survival in early embryos, as PFN1-KN could induce Drosophila embryos to die at the 2-cell stage.94 For further investigation of PFN1s roles in tissue-specific stem cells, Zheng et al established PFN1flox/flox mice that inducibly delete PFN1 in HSCs. Results showed that PFN1 was essential for the retention and metabolism of mouse hematopoietic stem cells in bone marrow partially through the axis of PFN1/G13/EGR1.95 These study results implied important roles of PFN1 in stem cell function, which were still unclear and deserved further research. Later study results have found that both overexpression and depletion of PFN1 could reduce the stem-like phenotype of MDA-MB-231 (MDA-231) triple-negative breast cancer cells, suggesting that a balanced expression of PFN1 was required for maintenance of optimal stemness and tumor-initiating ability of breast cancer cells.93 Considering that tumor heterogeneity is still an ongoing challenge for cancer treatment and that cancer stem cells (CSC) are considered to be a determining factor of tumor heterogeneity,96 intensive studies on PFN1s roles in CSC may provide us new insight into tumor initiation.

As mentioned above, PFN1 has been shown to be a critical participator of actin dynamics and to play important roles in cell migration. For cytotoxic T lymphocytes (CTLs), migration abilities are essential for patrolling tissues and locating targeted cells.97-98 Schoppmeyer et al thus studied PFN1s roles in CTL functions. The authors found that PFN1 negatively regulated CTL-mediated elimination of target cells and that PFN1 downregulation promoted CTL invasion into a 3D matrix in vitro. In patients with pancreatic cancer, PFN1 expression was substantially decreased in peripheral CD8+ T cells.99 However, considering the complexity of immune responses in vivo, the exact roles of PFN1 in tumor immunity remain unclear and need to be further explored.

Based on previous studies, we found that PFN1participates in multiple biological processes of tumor development and progression. Meanwhile, it is noteworthy that PFN1 plays opposite roles in different tumors and at different periods of tumor, potentially leading to the conclusion that PFN1s function in tumor has spatial and temporal specificity. Future studies on PFN1 should take this into account. PFN1 was shown to be of great significance for diagnosis and prognosis prediction and for monitoring the therapeutic effect of anticancer drugs, and PFN1s roles in tumor stemness and immunity may provide a new avenue for cancer therapy. Although much research has been done on PFN1 and cancer, puzzles still need to be solved. With deepening research, the function of PFN1 in cancer would be further clarified and its clinical value would be more prominent.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Conflicts of Interest: Authors declare no conflicts of interest for this article.

Acknowledgment: The authors are thankful for financial support from the Doctoral Fund Project of Hunan Provincial Peoples Hospital (program number BSJJ201812).

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Profilin 1 Protein and Its Implications for Cancers - Cancer Network

After closing a merger with GX Acquisition Corp., Celularity Inc., a clinical-stage cellular medicine company, is taking the next step in its evolution to enable further development of novel, off-the-shelf allogeneic placentaderived cellular therapies.1

Celularity aims to transform the way we approach the treatment of cancer and other diseases by harnessing the versatility, unique immune biology, and innate stemness of placental-derived cells, Robert J. Hariri, MD, PhD, found, chairperson, and chief executive officer of Celularity, stated in a press release. We are immensely proud of our clinical development results so far as well as the state-of-the-art manufacturing capabilities we built to support rapid scaling and a competitive cost structure for our placental-derived cell therapeutics. We believe off-the-shelf, allogeneic cell therapies will drive a paradigm shift in how clinicians approach the treatment of cancer and other serious diseases.

CYNK-001, the companys lead product candidate, is the only cryopreserved, allogeneic, off-the-shelf natural killer (NK) cell therapy to be developed from placental hematopoietic stem cells. The agent expresses perforin and granzyme B, has showcased cytotoxic activity against hematological tumors and solid tumor cell lines, and can secrete immunomodulatory cytokines in the presence of tumor cells.

The novel therapy is under investigation as a potential option in multiple myeloma, acute myeloid leukemia (AML), and glioblastoma multiforme; it is also being evaluated in infectious diseases like COVID-19 (NCT04365101).

An ongoing, open-label, multi-dose, phase 1 trial (NCT04310592) is examining the maximum-tolerated dose (MTD) or maximum planned dose of CYNK-001 in an estimated 22 patients with acute myeloid leukemia (AML).2 To participate, patients need to have primary or secondary AML and be in first or second morphological clinical response (CR), morphological CR with incomplete hematologic recovery, or a morphologic leukemia-free state per European LeukemiaNet recommendations for AML Response Criteria.

Patients also need to have MRD positivity, be aged between 18 and 80 years old, have an ECOG performance status of 0 to 2, and be able to be off immunosuppressive therapy for at least 3 days before infusion with the therapy. Patients who previously had central nervous system involvement are allowed to enroll if they had been treated and their cerebral spinal fluid is clear for at least 2 weeks before undergoing lymphodepletion.

Exclusion criteria include significant medical conditions, laboratory abnormalities, bi-phenotypic acute leukemia, acute promyelocytic leukemia, unacceptable organ function, autoimmune disease, uncontrolled graft-vs-host disease (GVHD), and GVHD that requires corticosteroids.

Participants are first given cyclophosphamide plus fludarabine. Then, they are administered CYNK-001 at 3 varying dose levels1.8 billion, 3.6 billion, and 5.4 billion CYNK-001 cellson days 0, 7, and 14. The primary objectives of the research include dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and frequency and severity of adverse effects. Important secondary objectives include the number of patients who convert from MRD-positive to -negative status; time to, and duration of, MRD response; progression-free survival; time to progression; duration of morphologic complete remission; and overall survival.

In June 2021, the study was expanded to include patients with relapsed/refractory AML following a case of conversion to MRD negativity, when the therapy was delivered at its highest dose level.3

The decision to expand the trial followed observations of a patient with NPM-1positive, FLT3-negative AML and good-risk cytogenetics who had been administered 5.4 billion CYNK-001 cells. The patient converted from MRD-positive to -negative status, without experiencing any DLTs.

For this patient, primary induction treatment with 7+3 chemotherapy had failed, and so they had gone on to receive second induction therapy followed by high-dose cytarabine consolidation. At this time point, the patient achieved a complete CR, but MRD was found to be persistent; it did not clear following 4 months of treatment with azacitidine. MRD positivity was confirmed on a marrow biopsy.

The patient went on to enter the phase 1 trial, where they received lymphodepletion, and then received 1.8 billion CYNK-001 cells on days 0, 7, and 14 in the outpatient setting, which totaled to 5.4 billion CYNK-001 cells. On day 28, the patient had converted from MRD positivity to negativity. CYNK-001 cells were present in both the peripheral blood and bone marrow.

Notably, no DLTs have been observed with the therapy at any of the dose levels examined thus far.

The company also shared plans to continue dose escalation with the therapy in the MRD indication up to 9.0 billion CYNK-001 cells. To strengthen the persistence of the treatment, the expansion arms of MRD and relapsed/refractory AML will include an augmented lymphodepletion protocol comprised of cyclophosphamide at 3600 mg and fludarabine at 120 mg over 4 days vs cyclophosphamide at 900 mg plus fludarabine at 75 mg over 3 days.

In April 2021, the FDA granted an orphan drug designation to CYNK-001 as a potential therapeutic option for patients with malignant gliomas.4 As such, the therapy is also under investigation in patients with glioblastoma multiforme as part of another phase 1 trial (NCT04489420).5

To be eligible for enrollment, patients need to have historically confirmed disease at first or second relapse, measurable disease, a Karnofsky performance status of 60 or higher, and acceptable organ function, among other criteria.

Patients who previously received radiation within 12 weeks of their screening MRI; those who were on growth factors with less than 4 weeks of a washout period; those treated with radiotherapy, chemotherapy, or other investigational drugs within 4 weeks; those who received prior cellular or gene therapy; and those with active autoimmune disease, were excluded.

Cohort 1A of the trial will enroll up to 6 patients with recurrent glioblastoma multiforme who will receive intravenous CYNK-001 at a dose of 1.2 x 109 cells on days 0, 7, and 14. From the initial infusion of therapy, patients will be followed for a 42-day DLT period. No other interventions are planned between the last day of treatment.

If DLTs are experienced, cohort 1C, the de-escalation cohort, will include up to 6 patients with recurrent glioblastoma multiforme who will receive the therapy at a dose of 600 x 106 cells on days 0, 7, and 14. These patients will also be followed for DLTs for 42 days post infusion. Cohort 1B, the surgical cohort, will also enroll up to 6 patients, who will be given CYNK-001 at a maximum safe dose of either 1.2 x 109 cells or 600 x 106 cells at days 0, 7, and 14. Patients in this cohort will undergo resection following the last dose of the therapy in the DLT period.

Treatment of cohorts 2A or 2C will only begin after the safety data from cohorts 1A or 1C are determined to be acceptable. Here, patients will first have the Ommaya catheter placement in accordance with institutional policy within 1 week before CYNK-001 infusion on day 0. Cohort 2A will enroll up to 6 patients with recurrent glioblastoma multiforme who will be given the therapy at a dose of 200 x 106 cells +/- 50 x 106 cells intratumorally on day 0, 7, and 14.

Cohort 2C will also include up to 6 patients with recurrent disease who will receive the product at a dose of 200 x 106 cells +/- 50 x 106 cells intratumorally on day 0 and day 7. Lastly, cohort 2B, the surgical intratumoral cohort, will include 6 patients with glioblastoma multiforme who will receive the cellular therapy at a maximum safe dose of either 200 x 106 cells +/- 50 x 106 cells on day 0 and 7.

The primary objectives of the trial are to examine the number of patients who report DLTs with the therapy and toxicities. Important secondary objectives are to evaluate the overall response rate, duration of response, progression-free survival, time to progression, and overall survival.

The safety and efficacy of the cell therapy is also being explored in newly diagnosed patients with multiple myeloma after autologous stem cell transplant, as part of another phase 1 trial (NCT04309084).6 The objective of the program is to achieve durable responses with the therapy in these patients with multiple myeloma who are eligible for transplant in the first-line setting.

Another novel agent in the pipeline is CYNK-101, which is manufactured from NK cells extracted from postpartum placentas. The cells are then genetically engineered to boost cell-killing activity when given with a monoclonal antibody.7 Preclinical data with the product in combination with an antibody showed that the regimen resulted in cell-killing activity when administered to lymphoma cells in vitro.

Additionally, CYNK-CAR products are being developed as allogeneic, off-the-shelf strategies by modifying genes of the human placental hematopoietic stem cellderived NK cells. Several CAR constructs that are designed to target hematologic and solid tumor indications are currently under investigation.

Read more:
Developmental Interest in Allogeneic PlacentaDerived Cell Therapies Expands - OncLive

Imagine being able to reverse blindness, cure multiple sclerosis (MS), or rebuild your heart muscles after a heart attack. For the past few decades, research into stem cells, the building blocks of tissues and organs, has raised the prospect of medical advances of this kind yet it has produced relatively few approved treatments. But that could be about to change, says Robin Ali, professor of human molecular genetics of Kings College London. Just as gene therapy went from being a fantasy with little practical value to becoming a major area of treatment, stem cells are within a few years of reaching the medical mainstream. Whats more, developments in synthetic biology, the process of engineering and re-engineering cells, could make stem cells even more effective.

Stem cells are essentially the bodys raw material: basic cells from which all other cells with particular functions are generated. They are found in various organs and tissues, including the brain, blood, bone marrow and skin. The primary promise of adult stem cells lies in regenerative medicine, says Professor Ali.

Stem cells go through several rounds of division in order to produce specialist cells; a blood stem cell can be used to produce blood cells and skin stem cells can be used to produce skin cells. So in theory you can take adult stem cells from one person and transplant them into another person in order to promote the growth of new cells and tissue.

In practice, however, things have proved more complicated, since the number of stem cells in a persons body is relatively limited and they are hard to access. Scientists were also previously restricted by the fact that adult stem cells could only produce one specific type of cell (so blood stem cells couldnt produce skin cells, for instance).

In their quest for a universal stem cell, some scientists initially focused on stem cells from human embryos, but that remains a controversial method, not only because harvesting stem cells involves destroying the embryo, but also because there is a much higher risk of rejection of embryonic stem cells by the recipients immune system.

The good news is that in 2006 Japanese scientist Shinya Yamanaka of Kyoto University and his team discovered a technique for creating what they call induced pluripotent stem cells (iPSC). The research, for which they won a Nobel Prize in 2012, showed that you can rewind adult stem cells development process so that they became embryo-like stem cells. These cells can then be repurposed into any type of stem cells. So you could turn skin stem cells into iPSCs, which could in turn be turned into blood stem cells.

This major breakthrough has two main benefits. Firstly, because iPSCs are derived from adults, they dont come with the ethical problems associated with embryonic stem cells. Whats more, the risk of the body rejecting the cells is much lower as they come from another adult or are produced by the patient. In recent years scientists have refined this technique to the extent that we now have a recipe for making all types of cells, as well as a growing ability to multiply the number of stem cells, says Professor Ali.

Having the blueprint for manufacturing stem cells isnt quite enough on its own and several barriers remain, admits Professor Ali. For example, we still need to be able to manufacture large numbers of stem cells at a reasonable cost. Ensuring that the stem cells, once they are in the recipient, carry out their function of making new cells and tissue remains a work in progress. Finally, regulators are currently taking a hard line towards the technology, insisting on exhaustive testing and slowing research down.

The good news, Professor Ali believes, is that all these problems are not insurmountable as scientists get better at re-engineering adult cells (a process known as synthetic biology). The costs of manufacturing large numbers of stem cells are falling and this can only speed up as more companies invest in the area. There are also a finite number of different human antigens (the parts of the immune system that lead a body to reject a cell), so it should be possible to produce a bank of iPSC cells for the most popular antigen types.

While the attitude of regulators is harder to predict, Professor Ali is confident that it needs only one major breakthrough for the entire sector to secure a large amount of research from the top drug and biotech firms. Indeed, he believes that effective applications are likely in the next few years in areas where there are already established transplant procedures, such as blood transfusion, cartilage and corneas. The breakthrough may come in ophthalmology (the treatment of eye disorders) as you only need to stimulate the development of a relatively small number of cells to restore someones eyesight.

In addition to helping the body repair its own tissues and organs by creating new cells, adult stem cells can also indirectly aid regeneration by delivering other molecules and proteins to parts of the body where they are needed, says Ralph Kern, president and chief medical officer of biotechnology company BrainStorm Cell Therapeutics.

For example, BrainStorm has developed NurOwn, a cellular technology using peoples own cells to deliver neurotrophic factors (NTFs), proteins that can promote the repair of tissue in the nervous system. NurOwn works by modifying so-called Mesenchymal stem cells (MSCs) from a persons bone marrow. The re-transplanted mesenchymal stem cells can then deliver higher quantities of NTFs and other repair molecules.

At present BrainStorm is using its stem-cell therapy to focus on diseases of the brain and nervous system, such as amyotrophic lateral sclerosis (ALS, also known as Lou Gehrigs disease), MS and Huntingtons disease. The data from a recent final-stage trial suggests that the treatment may be able to halt the progression of ALS in those who have the early stage of the disease. Phase-two trial (the second of three stages of clinical trials) of the technique in MS patients also showed that those who underwent the treatment experienced an improvement in the functioning of their body.

Kern notes that MSCs are a particularly promising area of research. They are considered relatively safe, with few side effects, and can be frozen, which improves efficiency and drastically cuts down the amount of bone marrow that needs to be extracted from each patient.

Because the manufacture of MSC cells has become so efficient, NurOwn can be used to get years of therapy in one blood draw. Whats more, the cells can be reintroduced into patients bodies via a simple lumbar puncture into the spine, which can be done as an outpatient procedure, with no need for an overnight stay in hospital.

Kern emphasises that the rapid progress in our ability to modify cells is opening up new opportunities for using stem cells as a molecular delivery platform. Through taking advantage of the latest advances in the science of cellular therapies, BrainStorm is developing a technique to vary the molecules that its stem cells deliver so they can be more closely targeted to the particular condition being treated. BrainStorm is also trying to use smaller fragments of the modified cells, known as exosomes, in the hope that these can be more easily delivered and absorbed by the body and further improve its ability to avoid immune-system reactions to unrelated donors. One of BrainStorms most interesting projects is to use exosomes to repair the long-term lung damage from Covid-19, a particular problem for those with long Covid-19. Early preclinical trials show that modified exosomes delivered into the lungs of animals led to remarkable improvements in their condition. This included increasing the lungs oxygen capacity, reducing inflammation, and decreasing clotting.

Overall, while Kern admits that you cant say that stem cells are a cure for every condition, there is a lot of evidence that in many specific cases they have the potential to be the best option, with fewer side effects. With Americas Food and Drug Administration recently deciding to approve Biogens Alzheimers drug, Kern thinks that they have become much more open to approving products in diseases that are currently considered untreatable. As a result, he thinks that a significant number of adult stem-cell treatments will be approved within the next five to ten years.

Adult stem cells and synthetic biology arent just useful in treatments, says Dr Mark Kotter, CEO and founder of Bit Bio, a company spun out of Cambridge University. They are also set to revolutionise drug discovery. At present, companies start out by testing large numbers of different drug combinations in animals, before finding one that seems to be most effective. They then start a process of clinical trials with humans to test whether the drug is safe, followed by an analysis to see whether it has any effects.

Not only is this process extremely lengthy, but it is also inefficient, because human and animal biology, while similar in many respects, can differ greatly for many conditions. Many drugs that seem promising in animals end up being rejected when they are used on humans. This leads to a high failure rate. Indeed, when you take the failures into account, it has been estimated that it may cost as much to around $2bn to develop the typical drug.

As a result, pharma companies are now realising that you have to insert the human element at a pre-clinical stage by at least using human tissues, says Kotter. The problem is that until recently such tissues were scarce, since they were only available from biopsies or surgery. However, by using synthetic biology to transform adult stem cells from the skin or other parts of the body into other types of stem cells, researchers can potentially grow their own cells, or even whole tissues, in the laboratory, allowing them to integrate the human element at a much earlier stage.

Kotter has direct experience of this himself. He originally spent several decades studying the brain. However, because he had to rely on animal tissue for much of his research he became frustrated that he was turning into a rat doctor.

And when it came to the brain, the differences between human and rat biology were particularly stark. In fact, some human conditions, such as Alzheimers, dont even naturally appear in rodents, so researchers typically use mice and rats engineered to develop something that looks like Alzheimers. But even this isnt a completely accurate representation of what happens in humans.

As a result of his frustration, Kotter sought a way to create human tissues. It initially took six months. However, his company, Bit Bio, managed to cut costs and greatly accelerate the process. The companys technology now allows it to grow tissues in the laboratory in a matter of days, on an industrial scale. Whats more, the tissues can also be designed not just for particular conditions, such as dementia and Huntingdons disease, but also for particular sub-types of diseases.

Kotter and Bit Bio are currently working with Charles River Laboratories, a global company that has been involved in around 80% of drugs approved by the US Food and Drug Administration over the last three years, to commercialise this product. They have already attracted interest from some of the ten largest drug companies in the world, who believe that it will not only reduce the chances of failure, but also speed up development. Early estimates suggest that the process could double the chance of a successful trial, effectively cutting the cost of each approved drug by around 50% from $2bn to just $1bn. This in turn could increase the number of successful drugs on the market.

Two years ago my colleague Dr Mike Tubbs tipped Fate Therapeutics (Nasdaq: FATE). Since then, the share price has soared by 280%, thanks to growing interest from other drug companies (such as Janssen Biotech and ONO Pharmaceutical) in its cancer treatments involving genetically modified iPSCs.

Fate has no fewer than seven iPSC-derived treatments undergoing trials, with several more in the pre-clinical stage. While it is still losing money, it has over $790m cash on hand, which should be more than enough to support it while it develops its drugs.

As mentioned in the main story, the American-Israeli biotechnology company BrainStorm Cell Therapeutics (Nasdaq: BCLI) is developing treatments that aim to use stem cells as a delivery mechanism for proteins. While the phase-three trial (the final stage of clinical trials) of its proprietary NurOwn system for treatment of Amyotrophic lateral sclerosis (ALS, or Lou Gehrigs disease) did not fully succeed, promising results for those in the early stages of the disease mean that the company is thinking about running a new trial aimed at those patients. It also has an ongoing phase-two trial for those with MS, a phase-one trial in Alzheimers patients, as well as various preclinical programmes aimed at Parkinsons, Huntingtons, autistic spectrum disorder and peripheral nerve injury. Like Fate Therapeutics, BrainStorm is currently unprofitable.

Australian biotechnology company Mesoblast (Nasdaq: MESO) takes mesenchymal stem cells from the patient and modifies them so that they can absorb proteins that promote tissue repair and regeneration. At present Mesoblast is working with larger drug and biotech companies, including Novartis, to develop this technique for conditions ranging from heart disease to Covid-19. Several of these projects are close to being completed.

While the US Food and Drug Administration (FDA) controversially rejected Mesoblasts treatment remestemcel-L for use in children who have suffered from reactions to bone-marrow transplants against the advice of the Food and Drug Administrations own advisory committee the firm is confident that the FDA will eventually change its mind.

One stem-cell company that has already reached profitability is Vericel (Nasdaq: VCEL). Vericels flagship MACI products use adult stem cells taken from the patient to grow replacement cartilage, which can then be re-transplanted into the patient, speeding up their recovery from knee injuries. It has also developed a skin replacement based on skin stem cells.

While earnings remain relatively small, Vericel expects profitability to soar fivefold over the next year alone as the company starts to benefit from economies of scale and runs further trials to expand the range of patients who can benefit.

British micro-cap biotech ReNeuron (Aim: RENE) is developing adult stem-cell treatments for several conditions. It is currently carrying out clinical trials for patients with retinal degeneration and those recovering from the effects of having a stroke. ReNeuron has also developed its own induced pluripotent stem cell (iPSC) platform for research purposes and is seeking collaborations with other drug and biotech companies.

Like other small biotech firms in this area, it is not making any money, so it is an extremely risky investment although the rewards could be huge if any of its treatments show positive results from their clinical trials.

Read more from the original source:
Investing in stem cells, the building blocks of the body - MoneyWeek

Corning HYPERStack 36-layer and 12-layer cell culture vessels

Mesenchymal stem cells (MSCs) are used frequently for cell therapy applications. As multipotent cells, they can differentiate into other lineages such as adipocytes, osteocytes, and chondrocytes. Additionally, they are known to secrete trophic factors that can play important roles in immunoregulation. Although MSCs can be isolated from several different tissue sources, those derived from bone marrow commonly are studied because they are easy to access in quantities large enough for therapeutic dosing (2 106 cells/kg of body weight). Still, that equates to 140 million cells for a 150-pound individual. And the process of expanding MSCs to achieve such quantities can introduce risks for heterogeneity-induced quality failures. Chances of clinical success can improve with a manufacturing process that maintains a homogeneous MSC population after expansion to meet required critical quality attributes (CQAs).

Once cells are scaled up, they need to be cryopreserved for stability and transport. Cryoprotectants such as dimethyl sulfoxide (DMSO) often are added to freezing media to reduce ice formation and increase cell survival after thawing. However, because DMSO can be cytotoxic, its final concentration in a drug product must be minimized. Tools from Corning Life Sciences can help scientists and drug developers meet growing demand for bone-marrowderived MSC therapies.

Figure 1:Expansion of human mesenchymal stem cells (MSCs) in a Corning HYPERStack-36 vessel; MSC densities ranging from 4.4 104 to 5.2 104 cells/cm2 were achieved after five days of culture. Across three studies, total MSC yield averaged 8.7 108 cells per HYPERStack-36 vessel, with >90% average MSC viability.

Mesenchymal Cell Scale-UpMSCs are adherent cells that are sensitive to manufacturing process changes. That sensitivity can complicate scale-up to large quantities. When cultured under suboptimal conditions, MSCs can lose their multipotency. Corning HYPERStack 36-layer cell culture vessels offer a solution. A HYPERStack unit uses proprietary technology to provide a large surface area in a compact footprint. That technology relies on an ultrathin, gas-permeable film to facilitate gas exchange in each layer of the vessel. Each HYPERStack module comprises 12 individual chambers featuring Corning CellBIND surface treatment for optimal cell attachment. One module provides 6,000 cm2 of surface area; three modules can connect to form a HYPERStack 36-layer vessel, totaling 18,000 cm2 of growth surface area.

When human bone-marrowderived MSCs are cultured in a HYPERStack 36-layer vessel, yields of >800 million viable cells can be achieved (Figure 1). Harvested cells show high viability and expression of markers demonstrating MSC multipotency (Figure 2). Such results show that large-scale expansion of MSCs in a HYPERStack vessel generates a homogeneous population of cells that maintain necessary CQAs.

Figure 2: Mesenchymal stem cells (MSCs) recovered from a Corning HYPERStack 36-layer cell culture vessels show >99% expression of CD90, CD105, and CD73 markers while expressing <0.5% of differentiation markers (CD45, CD34, CD11b, CD19, and HLA-DR).

Corning cryopreservation bags remain flexible at ultralow temperatures(e.g., 196 C).

Large-Scale CryopreservationCryopreservation of large quantities of cells has become an important strategy for simplifying cell therapy workflows because it increases product shelf life, allows time for quality testing, and lengthens the period of potential administration. Cryopreservation bags are designed for single-use storage, preservation, and transfer of large volumes of cells. Cornings cryopreservation bags are novel bag-film containers that can remain flexible at ultralow temperatures (196 C) because they are made from a proprietary polyolefinethyl vinyl acetate blend. Corning produces the bags in four sizes covering fill volumes between 20 mL and 190 mL, with demonstrated performance for storage of bone-marrowderived MSCs.

The Corning X-WASH system performs DMSO removal in a closed, sterile format.

DMSO RemovalDMSO can serve as a cryoprotectant for a wide range of cell types. It often accounts for 510% of a freezing solution to reduce ice formation and maintain cell viability. But because of its cytotoxic effects, DMSO must be removed as much as possible from a final cell therapy product. That can be accomplished by centrifugation and buffer exchange.

The Corning X-WASH system can perform those steps in sterile, closed conditions (Figure 3). The X-WASH system also uses highly sensitive infrared sensors and software to transfer process data from the X-WASH control module to a database. That feature supports good manufacturing practice (GMP) data processing, monitoring, and reporting. Ultimately, the X-WASH system is designed to wash, resuspend, and condense cell suspensions without compromising product quality.

Corning has used the X-WASH system to reduce the DMSO concentration from a bone-marrowderived MSC product. About 70 million human MSCs were processed into Corning cryopreservation bags containing 10 mL of a 90% fetal bovine serum (FBS) and 10% DMSO solution. MSCs were thawed into 200 mL of phosphate-buffered saline containing 2% human serum albumin and 5% glucose. Cells were added to X-WASH cartridges for processing, then analyzed for recovery (Figure 4), viability (Figure 5), and multipotency (Figure 6). Ultraperformance liquid chromatography (UPLC) was used to quantify DMSO reduction. UPLC analysis showed that 200-mL dilution followed by a 200-mL wash in an X-WASH system reduced the final DMSO concentration by at least40 fold.

Figure 3:Corning X-WASH system workflow to remove dimethyl sulfoxide (DMSO)

Figure 4:Recovery of human mesenchymal stem cells (MSCs) after washing with a Corning X-WASH system; the bars below represent MSC density, and cell viability levels are represented as dots.

Considerations for Closed Systems and Custom MediaClosed-system cell-culture products help reduce contamination risks during drug development and manufacturing. Thus, they should be considered when planning for cell-culture operations. Ordering multiple components and assembling tubing sets in house can add complexity and time to cell therapy processes. To aid in the development of such processes, Corning offers preassembled closed systems and aseptic-transfer caps that are compatible with many Corning cell culture vessels.

Figure 5:Human MSC multipotency as represented by average marker expression after processing with a Corning X-WASH system (with standard deviation, n = 3)

Corning closed-system solutions arrive at your facility sterile and ready to use. They mitigate contamination risks, reduce the time and expense of sourcing and assembly, and improve overall productivity. Moreover, Cornings extensive library of fully validated filters, connectors, tubing, and clamps enables customized design of a closed-system solution for a specific application.

In cell-based therapies, cultured cells are the final product, requiring different manufacturing processes from those used for conventional biologics production. Major considerations in cell therapy scale-up include culture vessels and media as well as cells themselves. Inadequate attention to culture equipment and raw materials not only can diminish a therapys efficacy, but also can result in regulatory challenges that might delay a candidates progress through development. Because culture media are linked to cell growth and productivity, they rank among the most critical aspects of process development during scale-up.

Figure 6:Dimethyl sulfoxide (DMSO) concentration in final product after 200-mL dilution followed by 200-mL wash in a Corning X-WASH system (data from three independent runs)

Although off-the-shelf media can provide fast and efficient solutions during early stages, they can have trouble meeting specific scale-up conditions later on. Moving from small-scale, small-volume, static cultures into large-scale, large-volume vessels can trigger a host of additional requirements that cannot be addressed easily using an off-the-shelf solution. Customization by a media manufacturer is an attractive solution to concerns associated with large production scales, including media stability, packaging, handling, and storage. Custom media solutions also help to derisk processing. Cornings high-quality custom development and manufacturing services can produce tailored media and reagents to meet cell therapy production needs.

Simplifying Cell Therapy WorkflowsAddressing the growing demand for cell-based therapies requires optimization of scale-up, cryopreservation, and DMSO removal. With some human MSC therapies requiring as many as one billion cells per dose, cell therapy companies need efficient ways to scale up production of homogeneous MSCs that meet CQAs. Additionally, large quantities of MSCs will need to be cryopreserved to simplify cell therapy workflows. Before product administration, DMSO and other reagents used during the manufacturing process will need to be reduced. Corning offers solutions to simplify the complete range of cell therapy workflows.

Hilary Sherman is senior scientist, and Chris Suarez is field applications manager at Corning Life Sciences, 836 North Street, Tewksbury, MA 01876; ScientificSupport@Corning.com; 1-800-492-1110.

CellBIND, HYPERStack, and X-WASH all are registered trademarks of Corning Incorporated.

Read more:
Cell Therapy Workflows Using Corning HYPERStack: MSC Production - BioProcess Insider

The research report presents a comprehensive assessment of the Bone Marrow-Derived Stem Cells (BMSCS) Market and contains thoughtful insights, facts, historical data, and statistically supported and industry-validated market data. Bone Marrow-Derived Stem Cells (BMSCS) with 100+ market data Tables, Pie Chat, Graphs & Figures spread through Pages and easy to understand detailed analysis. Bone Marrow-Derived Stem Cells (BMSCS) market future, competitive analysis by Bone Marrow-Derived Stem Cells (BMSCS) Market Players, Deployment Models, Opportunities, Future Roadmap, Value Chain, Major Player Profiles.

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Bone marrow-derivedstem cells(BMSCS) market is expected to gain market growth in the forecast period of 2020 to 2027. Data Bridge Market Research analyses the market to growing at a CAGR of 10.4% in the above-mentioned forecast period. Increasing awareness regarding the benefits associates with the preservation of bone marrow derived stem cells will boost the growth of the market.

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Bone Marrow-Derived Stem Cells (BMSCS) Market competition by top manufacturers/players, with sales volume, Price (USD/Unit), Revenue (Million USD) and market share for each manufacturer/player; the top players including:

CBR Systems, Inc, Cordlife Sciences India Pvt. Ltd., Cryo-Cell International, Inc.ESPERITE N.V., LifeCell International Pvt. Ltd., StemCyte India Therapeutics Pvt. Ltd, PerkinElmer Inc, Global Cord Blood Corporation., Smart Cells International Ltd., Vita 34 among other domestic and global players. .

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Bone Marrow-Derived Stem Cells (BMSCS) Market Global Briefing and Future Outlook 2020 to 2027 The Courier - The Courier

The Global Rheumatoid Arthritis Stem Cell Therapy Market Research Report 2020-2026, offers an in-depth evaluation of each crucial aspect of the Global Rheumatoid Arthritis Stem Cell Therapy industry that relates to market size, share, revenue, demand, sales volume, and development in the market. The report analyzes the Rheumatoid Arthritis Stem Cell Therapy market related to the time period, historical pricing structure, and volume trends that make it easy to predict growth momentum and precisely estimate forthcoming opportunities in the Rheumatoid Arthritis Stem Cell Therapy Market. The report explores the current outlook in global and key regions (North America, Europe, Asia-Pacific, and Latin America) from the perspective of players, countries (U.S., Canada, Germany, France, U.K., Italy, Russia, China, Japan, South Korea, Taiwan, Southeast Asia, Mexico, and Brazil, etc.), product types, and end use segments. This report provides the COVID-19 (Corona Virus) impact analysis (historic and present) in major regions and countries, also provides a futuristic analysis considering COVID-19.

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Rheumatoid Arthritis Stem Cell Therapy Market Size, Status and Precise Outlook During 2020 to 2026 The Manomet Current - The Manomet Current

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

Patients with blood cancers are particularly vulnerable to COVID-19, and there has been concern that such patients mount poor responses to COVID vaccination.

Perhaps surprising, then, is a new study showing good responses in a subgroup of these patients who underwent intensive treatment with allogeneic hematopoietic stem cell transplant (HCT) or chimeric antigen receptor T-cell (CAR-T) therapy

These patients had relatively good responses to COVID-19 vaccination with the mRNA vaccine, with overall cellular and humoral responses that were near to or over 80%.

"I was actually surprised by the fact patients who underwent allogeneic HCT and are currently treated with immunosuppression medications had a such high response to the vaccine," first author Ron Ram, MD, director of the Bone Marrow Transplantation Unit, Division of Hematology, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel, told Medscape Medical News.

"In other seasonal vaccines, we usually see much lower responses," he noted. "The problem is that we are not sure how long this response lasts, and this should be further investigated."

The results show that among immunocompromised patients, "the vaccine is safe and efficacious," he concluded.

However, "5% of patients developed transient severe low counts and graft-vs-host disease [GVHD] exacerbation. Therefore, close monitoring of these patients is mandatory.

"COVID-19 is a very dangerous infection to our allogeneic and CAR-T patients, and all patients should be vaccinated as soon as possible," he added.

The study was presented at the European Hematology Association (EHA) 2021 Annual Meeting. It involved 79 eligible patients who received hematopoietic cell transplant (n = 66) and CAR T-cell therapy (n = 14) at the Tel Aviv Sourasky Medical Center.

The patients in the study were being treated for acute myeloid leukemia (46%), myelodysplastic syndromes (9%), acute lymphocytic leukemia (10%), diffuse large B-cell lymphoma (15%); and others.

All patients were vaccinated with the Pfizer/BioNTech BNT162b2 COVID-19 vaccine, which yielded a protection rate of 94.6% in a phase 3 study in healthy patients and is recommended for immunosuppressed patients.

The median age of the patients was 65 years, and the median time from infusion of cells to vaccination was 32 months in the allogeneic HCT group and 9 months in the CAR T-cell therapy group.

Of the allogeneic HCT patients, 62% had active chronic GVHD, and 58% were receiving immune suppressive therapy, mostly calcineurin inhibitors.

In addition, 11% of the patients overall had complete B-cell aplasia.

An evaluation of humoral immune responses to the vaccines at 7 to 14 days after the second vaccine dose, as determined on the basis of serology, showed that 82% of those in the allogeneic HCT group developed immunogenicity. However, the humoral response rate was only 36% in the CAR T-cell group.

When including the results cellular responses, assessed with the ELISpot assay, the tables were nearly turned, with the antibody titer response rate of 46% in the allogeneic HCT group and 79% in the CAR T-cell group.

Combined, the overall antibody responses were 86% of allogeneic HCT patients and 79% of CAR T-cell patients, Ram reported.

A multivariate analysis showed that factors associated with a positive humoral response included increased amount of time from the infusion of cells (P = .032), female sex (P = .028), and a higher number of CD19-positive cells (P = .047).

Age, active GVHD, and the intensity of concomitant immunosuppressive therapy were not predictive of results.

Ram noted that higher numbers of CD19-positive cells and CD4 cells were predictive of positive ELISpot cellular response (P = 0.49 and P = .041, respectively).

Two patients developed SARS-CoV-2 infection after receiving the first dose of the vaccine, although they did not require hospitalization. After fully recovering, both patients received a second dose.

The vaccine was well tolerated among patients in general. Side effects were similar to those observed in the nontransplant population.

Of the patients overall, 5% experienced GVHD exacerbation after each vaccine dose.

A low blood count was observed in about 10% of patients; in 5%, the cytopenia was severe.

Adverse events that were of grade 3 or higher occurred in 4.6% and 7% of the two groups, respectively. Although the adverse events resolved quickly in most cases, one secondary graft rejection occurred; that case is being investigated.

The European Society for Blood and Marrow Transplantation (EBMT) recommends vaccination starting at least 3 months after allogeneic HCT, and Ram said the recommendation "makes sense."

"We did see a nice response in the allogeneic HCT patients 3 months after the transplant," he said.

Exceptions were patients receiving anti-CD19 therapy in the CAR T-cell group and those with B-cell aplasia. "Those patients did not respond well to the vaccine, so this is something to take into consideration," Ram said.

"We certainly need more data about durability of the vaccine and methods in patients who do not have sufficient response to the vaccine."

The EBMT's recommendation on the timing of vaccination is endorsed by the National Comprehensive Cancer Network, which recommends that COVID-19 vaccination be delayed for at least 3 months for patients with allogeneic HCT or those undergoing CAR-T therapy.

In commenting on the study during a press conference, Elizabeth Macintyre, MD, said the new findings were encouraging.

"It's very precious to see consensus recommendations regarding who should be vaccinated and when, and the end result seems to be that it's better to be vaccinated than not," she said.

In a separate talk at the meeting, Evangelos Terpos, MD, PhD, reported finding lower response rates to COVID-19 vaccination among older patients with hematologic malignancies in general, consistent with findings from other studies.

Reporting on responses up to day 50 post vaccination among 48 patients with multiple myeloma (median age, 83 years), 40% of patients did not achieve antibody titers above the level of 30% considered to represent positivity.

Among the 49% who did achieve antibody responses above levels of 50%, representing clinically relevant inhibition, the treatment factors that were associated with the higher response included treatment with lenalidomide. Treatment with daratumumab or anti-BCMA conjugates was associated with very low antibody responses.

He noted other research of 58 older patients with Waldenstrom macroglobulinemia or other low-grade lymphomas showed similarly low responses, particularly among those receiving anti-CD20 treatment, compared with healthy individuals.

"We found that patients with hematological malignancies or solid tumors have lower responses [to the COVID-19 mRNA vaccine], especially those under immunotherapy or targeted therapies, including anti-CD20, anti-CD38, anti-BCMA, Bruton kinase inhibitors, PDL-1 or PD-1 inhibitors," said Terpos, a professor of hematology at the National and Kapodistrian University of Athens School of Medicine, Athens, Greece.

Ram has disclosed no relevant financial relationships. Terpos has relationships with Janssen, Genesis/Celgene, Amgen, Novartis, Sanofi, and Takeda.

European Hematology Association (EHA) 2021 Annual Meeting: Abstract S285. Presented June 11, 2021.

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Good Response to COVID-19 Vaccine After HSCT and CAR T-cell Tx Medscape - Medscape

Data Bridge Market Research has recently added a concise research on theGlobal Stem Cell Manufacturing Market to depict valuable insights related to significant market trends driving the industry. The report features analysis based on key opportunities and challenges confronted by market leaders while highlighting their competitive setting and corporate strategies for the estimated timeline. The development plans, market risks, opportunities and development threats are explained in detail. The CAGR value, technological development, new product launches and Industry competitive structure is elaborated. As per study key players of this market are Thermo Fisher Scientific. Merck Group, Becton, Dickinson and Company. Holostem Advanced Therapies, JCR Pharmaceuticals, Organogenesis Inc and more.

The Global Stem Cell manufacturing Market is expected to gain market growth in the forecast period of 2020 to 2027. Data Bridge Market Research analyses the market to account to USD 18.59 billion by 2027 growing at a CAGR of 6.42% in the above-mentioned forecast period. The growing awareness towards diseases like cancer, hematopoietic disorders and degenerative disorders is going to drive the growth of the stem cell manufacturing market.

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Global Stem Cell Manufacturing Market, By Product (Stem Cell Line, Instruments, Culture Media, Consumables), Application (Research Applications, Clinical Applications, Cell and Tissue Banking), End Users (Hospitals and Surgical Centers, Pharmaceutical and Biotechnology Companies, Clinics, Community Healthcare, Others), Country (U.S., Canada, Mexico, Germany, Italy, U.K., France, Spain, Netherland, Belgium, Switzerland, Turkey, Russia, Rest of Europe, Japan, China, India, South Korea, Australia, Singapore, Malaysia, Thailand, Indonesia, Philippines, Rest of Asia-Pacific, Brazil, Argentina, Rest of South America, South Africa, Saudi Arabia, UAE, Egypt, Israel, Rest of Middle East & Africa) Industry Trends and Forecast to 2027

Healthcare Infrastructure growth Installed base and New Technology Penetration

Stem cell manufacturing market also provides you with detailed market analysis for every country growth in healthcare expenditure for capital equipment, installed base of different kind of products for stem cell manufacturing market, impact of technology using life line curves and changes in healthcare regulatory scenarios and their impact on the stem cell manufacturing market. The data is available for historic period 2010 to 2018.

The Global Stem Cell Manufacturing Market is highly fragmented and the major players have used various strategies such as new product launches, expansions, agreements, joint ventures, partnerships, acquisitions, and others to increase their footprints in this market. The report includes market shares of stem cell manufacturing market for global, Europe, North America, Asia Pacific and South America.

Global Stem Cell Manufacturing Market Scope and Market Size

Stem cell manufacturing market is segmented on the basis of product, application and end users. The growth amongst these segments will help you analyse meagre growth segments in the industries, and provide the users with valuable market overview and market insights to help them in making strategic decisions for identification of core market applications.

Major Market competitors/players:Global Stem Cell manufacturing Market

Some of the major players operating in the stem cell manufacturing market are Thermo Fisher Scientific. Merck Group, Becton, Dickinson and Company. Holostem Advanced Therapies, JCR Pharmaceuticals, Organogenesis Inc, Osiris Therapeutics, Osiris Therapeutics, Vericel Corporation, AbbVie, American CryoStem, AM-Pharma, Anterogen.Co.,Ltd, Astellas Pharma, Bristol-Myers Squibb, Apceth Biopharma, Cellular Dynamics International, Rheacell, Takeda Pharmaceutical, Teva Pharmaceutical Industries Ltd. ViaCyte, VistaGen Therapeutics Inc, Translational Biosciences, GlaxoSmithKline plc, Daiichi Sankyo Company, Limited, among others.

Market Definition:

This market report defines the market trends and forecast the upcoming opportunities and threats of the stem cell manufacturing market in the next 8 years. Stem cell manufacturing is a process of extracting the cells either from bone marrow or peripheral blood cells and culturing the cells in the culture dish containing nutrient media. Stem cells can be isolated from umbilical cord blood, placenta, amniotic sac, amniotic fluid, adipose tissue and menstrual blood. Stem cell manufacturing is used in the cell therapy as well as in gene therapy. Stem cell therapy is under research for many diseases like degenerative diseases and hematopoietic disorders like sickle cell anemia, storage disorders. Now stem cells are also used in making the cell and tissue bank. Some of the cell culture banks are National Institute of Biomedical Innovation, Health and Nutrition and World Federation for Culture Collections.

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Stem Cell manufacturing Market All-Inclusive Research Report (20212027) : Includes Impact of COVID-19 The Manomet Current - The Manomet Current

Dublin, June 18, 2021 (GLOBE NEWSWIRE) -- The "Global Cell Isolation Market By Product (Consumables and Instruments), By Cell Type (Human Cells and Animal Cells), By Source, By Technique, By Application, By End-User, By Region, Competition Forecast & Opportunities, 2026" report has been added to ResearchAndMarkets.com's offering.

The Global Cell Isolation Market was valued at USD7013.71 million in 2020 and is anticipated to reach USD15529.45 million by 2026 by registering a CAGR of 15.25% until 2026.

Cell isolation is a technique of isolating cells for diagnosis and analysis of a particular type of cell. The market growth can be attributed to the rising demand for drugs, vaccines and other related products, as they are manufactured with the assistance of cell isolation technique. Increasing popularity of precision medicines is also working in the favor of the market growth.

The Global Cell Isolation Market has been segmented into product, cell type, source, technique, application, end-user, company and region. Based on technique, the market is further fragmented into centrifugation-based cell isolation, surface-marker based cell isolation and filtration-based cell isolation, amongst which, centrifugation-based cell isolation segment occupied the largest market share in 2020 as it finds extensive applications in various end-user sectors such as academic institutes, research laboratories, etc.

Based on application, the market is further divided into biomolecule isolation, cancer research, stem cell research, in vitro diagnostics and others. Among these, cancer research and stem cell research are projected to be the lucrative segments of the market in the forecast period. Increase in the research activities by biopharma companies and laboratory is the key factor for the growth of the segments.

Based on regional analysis, Asia-Pacific is expected to grow at the highest CAGR during the forecast period. The high CAGR of the region can be attributed to the relaxation in the stringent rules and regulations laid down by the government for drug development. Another factor that can be held responsible for the fastest growth of the region is the availability of competent researchers and personnel who can carry out cell isolation techniques along with a wide genome pool.

The market players are focusing on research and development activities in order to enhance their product portfolios and strengthen their position across the global market. For instance, the major pharmaceutical companies worldwide are making substantial investments in R&D to introduce new drugs in the market.

Such investments are expected to increase the demand for cell isolation products over the coming years. In addition to this, new product developments help vendors to expand their product portfolio and gain maximum share in the sector. For example, Thermo Scientific's Medifuge is a benchtop centrifuge which is having a unique hybrid rotor as well as an interchangeable swing-out buckets and fixed-angle rotors to facilitate rapid & convenient applications on a single platform.

Moreover, collaborations, mergers & acquisitions and regional expansions are some of the other strategic initiatives taken by major companies for serving the unmet needs of their customers.

Major players operating in the Global Cell Isolation Market include

Years considered for this report:

Objective of the Study:

Key Target Audience:

Report Scope:

Global Cell Isolation Market, By Product:

Global Cell Isolation Market, By Cell Type:

Global Cell Isolation Market, By Source:

Global Cell Isolation Market, By Technique:

Global Cell Isolation Market, By Application:

Global Cell Isolation Market, By End-User:

Global Cell Isolation Market, By Region:

Competitive Landscape

For more information about this report visit https://www.researchandmarkets.com/r/osam26

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Global $15.52 Bn Cell Isolation (Human Cells and Animal Cells) - GlobeNewswire

New York, June 01, 2021 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Stem Cell Market - Growth, Trends, COVID-19 Impact, and Forecasts (2021 - 2026)" - https://www.reportlinker.com/p06079777/?utm_source=GNW According to a 2020 research article published in the scientific journal Aging and Disease (2020), mesenchymal stem cells are a safe and effective approach to the treatment of COVID-19. At least 10 projects have been registered in the official international registry for clinical trials, implicating the use of mesenchymal stem cells to patients with coronavirus pneumonia. However, it is still at an initial stage of study in relation to the market studied.

Stem cells are majorly used in regenerative medicine, especially in the field of dermatology. However, oncology is expected to grow at the highest rate due to a large number of pipeline products present for the treatment of tumors or cancers. With the increase in the number of regenerative medicine centers, the stem cell market is also expected to increase in the future.

One of the richest sources of stem cells is the umbilical cord, which possesses unique qualities and has greater advantages over embryonic stem cells or adult stem cells. There are an increasing number of stem cell banks, which collaborate with hospitals and increase awareness about the storage of cord blood units in families, particularly in the emerging markets. The support is increasing with the rising number of medical communities and government initiatives active in promoting the use of stem cells for the treatment of more than 100 diseases. Currently, there is an increase in the number of clinical trials for testing future treatment possibilities of cord blood. Over 200 National Institutes of Health (NIH)-funded clinical trials with cord blood are currently being conducted in the United States alone.

Key Market TrendsThe Oncology Disorders Segment is Expected to Exhibit the Fastest Growth Rate Over the Forecast Period

The global cancer burden has been increasing, and thus, cancer therapies must be modified according to regional and national priorities. According to the World Cancer Research Fund, in 2018, there were an estimated 18 million cancer cases around the world. According to the World Health Organization (WHO), cancer is the second-leading cause of death across the world, with an estimated number of 9.6 million deaths in 2018, accounting for nearly one in six deaths.

Bone marrow transplant or stem cell transplant is a treatment for some types of cancer, like leukemia, multiple myeloma, neuroblastoma, or some types of lymphoma. For cancer treatments, both autologous and allogeneic stem cell transplants are done. Autologous transplants are preferred in the case of leukemias, lymphomas, multiple myeloma, testicular cancer, and neuroblastoma.

The major disadvantage associated with autologous stem cell transplants in cancer therapy is that cancer cells sometimes also get collected, along with stem cells, which may further put it back into the body during the therapy.

In case of allogeneic stem cell transplants, the donor can often be asked to donate more stem cells or even white blood cells, as per the requirement, and stem cells from healthy donors are free of cancer cells. However, the transplanted donor stem cells could die or be destroyed by the patients body before settling in the bone marrow.

Moreover, due to the growing focus of stem cell-based research and the rising demand for novel treatments, several companies, such as Stemline Therapeutics, have been focusing on developing technologies and treatments to attack cancer cells, which may help the market grow. However, owing to the COVID-19 pandemic, the detection and treatment of new cancer cases are impended, which may slightly impact the segment growth in the year.

North America Captured The Largest Market Share and is Expected to Retain its Dominance

North America dominated the overall stem cell market, with the United States contributing to the largest share in the market. The United States and Canada have developed and well-structured healthcare systems. These systems also encourage research and development. The increasing number of cancer cases is providing opportunities for market players. The major market players are focusing on R&D activities to introduce new stem cell therapies in the market.

For instance, the National Cancer Institute (NCI) had stated that the national expenditure on cancer care was expected to reach USD 156 billion by 2020. This factor is expected to boost the growth of the market in the future. In December 2019, the researchers at the National Eye Institute (NEI) launched a clinical trial to test the safety of a novel patient-specific stem cell-based therapy to treat geographic atrophy, the advanced dry form of age-related macular degeneration (AMD), a leading cause of vision loss among people aged 65 years and above.

In addition, the current situation of COVID-19 is another factor driving the growth of the market in the country, as research activities are undergoing for the treatment of COVID-19. Stem cell therapy can also be a promising approach for the treatment of COVID-19 in the future. For instance, on May 6, 2020, Lineage Cell Therapeutics received a grant of USD 5 million from the California Institute for Regenerative Medicine (CIRM) to support the use of VAC, Lineages allogeneic dendritic cell therapy for the development of a potential vaccine against SARS-CoV-2, the virus that causes COVID-19.

Competitive LandscapeThe stem cell market is highly competitive and consists of several major players. In terms of market share, few of the major players currently dominate the market. The presence of major market players, such as Thermo Fisher Scientific (Qiagen NV), Sigma Aldrich (a subsidiary of Merck KGaA), Becton, Dickinson and Company, and Stem Cell Technologies, is in turn, increasing the overall competitive rivalry in the market. The product advancements and improvement in stem cell technology by the major players are also increasing the competitive rivalry.

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The stem cell market was valued at USD 14.7 billion in 2020, and it is expected - GlobeNewswire

Brave Nathaniel Nabena smiles from his hospital bed moments before a life-saving procedure.

The nine-year-old had a vital stem cell transplant at Great Ormond Street Hospital on Wednesday after Sunday People readers helped raised more than 215,000.

Nathaniel, battling acute myeloid leukaemia, was on a drip for 30 minutes as umbilical cord stem cells were fed into his body.

Afterwards, dad Ebi said: Nathaniel is very happy. It was amazing to finally get to this point we have all been waiting for.

The youngster was admitted a fortnight ago and had five doses of chemo over ten days to prepare him for the procedure.

How brave has Nathaniel been? Have your say in comments below

Mum Modupe, 38, was able to spend time with him before his transplant.

Consultants warn he faces weeks of sickness as his body reacts to the new cells with symptoms including vomiting and a fever.

Ebi, 45, said: His doctors hope to see improvements after five weeks. It is so hard to see him so exhausted but I dont have a choice. We are grateful to have this done. Our fingers are crossed to see what happens.

For now, Nathaniel has a compromised immune system and is susceptible to falling ill, so he will be staying on the ward.

Stars including Simon Cowell, David Walliams, Katie Price and JLS singer Aston Merrygold rallied to support him after we told of the desperate race to fund treatment.

Nathaniels left eye was removed in his home country of Nigeria a year ago, due to myeloid sarcoma cancer. He was diagnosed with AML in the UK in November after coming here to have a prosthetic eye fitted.

Nathaniel was told a stem-cell transplant was his only hope for survival but it would cost 201,000 as he is not a British citizen. Ebi and Modupe were initially told it could cost as much as 825,000 but the figure was revised after doctors waived their fees and offered to treat him in their own time.

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The lad was admitted to GOSH on May 24 after generous Brits rushed to help the family raise cash.

Business analyst Ebi, who is staying at the hospitals family quarters, said: Ive been there the whole time. When he is not sleeping he is passing the time playing his games.

We sometimes talk about when he gets better and how exciting that will be. This is a difficult thing for him to go through, but Nathaniel is being brave, he is well in himself.

In acute myeloid leukaemia, unhealthy blood-forming stem cells grow quickly in the bone marrow.

This prevents it from making normal red blood cells, white blood cells and platelets meaning the body cannot fight infections or stop bleeding.

A stem cell transplant, also known as a bone marrow transplant, can help AML patients stimulate new bone marrow growth and restore the immune system.

Before treatment, patients need high doses of chemo and sometimes radiotherapy.

This destroys existing cancer and bone marrow cells and stops the immune system working, to cut the risk of transplant rejection.

In an allogeneic transplant, stem cells are taken from a family member, unrelated donor or umbilical cord blood. In Nathaniels case, it was from a cord.

They are then passed into the patients body through a line inserted in a large, central vein, in a process that takes up to two hours.

You can also remove stem cells from the patients body and transplant them later, after any damaged or diseased cells have been removed this is called an autologous transplant.

The survival rate after a transplant for patients with acute leukaemia in remission and using related donors is 55% to 68%, according to Medicine Net. If the donor is unrelated, it is 26% to 50%.

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Brave Nathaniel Nabena, 9, all smiles as he has life-saving procedure - thanks to you - The Mirror

Global Hematopoietic Stem Cell Transplantation (HSCT) Market Size, Status And Forecast 2021-2028

MarketInsightsReports, a leading global market research firm, is pleased to announce its new report on Hematopoietic Stem Cell Transplantation (HSCT) market, forecast for 2021-2028, covering all aspects of the market and providing up-to-date data on current trends.

The report covers comprehensive data on emerging trends, market drivers, growth opportunities, and restraints that can change the market dynamics of the industry. It provides an in-depth analysis of the market segments which include products, applications, and competitor analysis. The report also includes a detailed study of key companies to provide insights into business strategies adopted by various players in order to sustain competition in this highly competitive environment.

(Special Offer: Available Flat 30% Discount for a limited time only):Get a Free Sample Copy of the Report:https://www.marketinsightsreports.com/reports/06022956528/2016-2028-global-hematopoietic-stem-cell-transplantation-hsct-industry-market-research-report-segment-by-player-type-application-marketing-channel-and-region/inquiry?mode=dj

With our Hematopoietic Stem Cell Transplantation (HSCT) market research reports, we offer a comprehensive overview of this sector and its dynamics. We have done extensive research on this topic and are confident that our findings will be helpful for anyone who needs some guidance or direction when making important decisions related to their companys future growth strategy.

Top Companies in the Global Hematopoietic Stem Cell Transplantation (HSCT) Market: ViaCord Inc, Cryo-Save AG, CBR Systems Inc, Pluristem Therapeutics Inc, China Cord Blood Corp, Lonza Group Ltd, Escape Therapeutics Inc, Regen Biopharma Inc

This report segments the global Hematopoietic Stem Cell Transplantation (HSCT) market on the basis of Types are:

On the basis of Application, the Global Hematopoietic Stem Cell Transplantation (HSCT) market is segmented into:

For comprehensive understanding of market dynamics, the global Hematopoietic Stem Cell Transplantation (HSCT) market is analyzed across key geographies namely: United States, China, Europe, Japan, South-east Asia, India and others. Each of these regions is analyzed on basis of market findings across major countries in these regions for a macro-level understanding of the market.

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Key Takeaways from Hematopoietic Stem Cell Transplantation (HSCT) Report

Browse the report description and TOC: https://www.marketinsightsreports.com/reports/06022956528/2016-2028-global-hematopoietic-stem-cell-transplantation-hsct-industry-market-research-report-segment-by-player-type-application-marketing-channel-and-region?mode=dj

-Key Strategic Developments: The study also includes the key strategic developments of the market, comprising R&D, new product launch, M&A, agreements, collaborations, partnerships, joint ventures, and regional growth of the leading competitors operating in the market on a global and regional scale.

-Key Market Features: The report evaluates key market features, including revenue, price, capacity, capacity utilization rate, gross, production, production rate, consumption, import/export, supply/demand, cost, market share, CAGR, and gross margin. In addition, the study offers a comprehensive study of the key market dynamics and their latest trends, along with pertinent market segments and sub-segments.

-Analytical Tools: The Global Hematopoietic Stem Cell Transplantation (HSCT) Market report includes the accurately studied and assessed data of the key industry players and their scope in the market by means of a number of analytical tools. The analytical tools such as Porters five forces analysis, SWOT analysis, feasibility study, and investment return analysis have been used to analyze the growth of the key players operating in the market.

Customization of the Report: This report can be customized as per your needs for additional data up to 3 companies or countries or 40 analyst hours.

MarketInsightsReports provides syndicated market research on industry verticals including Healthcare, Information and Communication Technology (ICT), Technology and Media, Chemicals, Materials, Energy, Heavy Industry, etc.MarketInsightsReports provides global and regional market intelligence coverage, a 360-degree market view which includes statistical forecasts, competitive landscape, detailed segmentation, key trends, and strategic recommendations.

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Hematopoietic Stem Cell Transplantation (HSCT) Market Competitive Analysis with Global Trends and Demand 2021 to 2028:ViaCord Inc, Cryo-Save AG, CBR...

Abstract

Immunomodulatory drugs (IMiDs) have markedly improved patient outcome in multiple myeloma (MM); however, resistance to IMiDs commonly underlies relapse of disease. Here, we identify that tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) knockdown (KD)/knockout (KO) in MM cells mediates IMiD resistance via activation of noncanonical nuclear factor B (NF-B) and extracellular signalregulated kinase (ERK) signaling. Within MM bone marrow (BM) stromal cell supernatants, TNF- induces proteasomal degradation of TRAF2, noncanonical NF-B, and downstream ERK signaling in MM cells, whereas interleukin-6 directly triggers ERK activation. RNA sequencing of MM patient samples shows nearly universal ERK pathway activation at relapse on lenalidomide maintenance therapy, confirming its clinical relevance. Combination MEK inhibitor treatment restores IMiD sensitivity of TRAF2 KO cells both in vitro and in vivo. Our studies provide the framework for clinical trials of MEK inhibitors to overcome IMiD resistance in the BM microenvironment and improve patient outcome in MM.

Multiple myeloma (MM) is characterized by the infiltration of abnormal plasma cells in the bone marrow (BM) and monoclonal protein in serum and/or urine, associated with hypercalcemia, renal dysfunction, anemia, and bone disease (1). The development of high-dose therapy and autologous stem cell transplantation (2, 3) and, more recently, of novel agents including proteasome inhibitors (4), histone deacetylase inhibitor (5, 6), immunomodulatory drugs (IMiDs) (79), and monoclonal antibodies (Abs) (1012), has transformed therapy and markedly improved patient outcome.

The IMiD thalidomide (Thal) was banned because of its teratogenicity when prescribed to treat morning sickness of pregnant women 50 years ago (13). However, Thal and its analogs lenalidomide (Len) and pomalidomide (Pom), initially used empirically predicated upon their antiangiogenic activity (14), have demonstrated remarkable clinical efficacy in MM and other B cell malignancies (15). Our early studies showed that IMiDs trigger direct MM cytotoxicity via activation of caspase-8mediated extrinsic apoptotic pathway, as well as enhancing immune effector antitumor responses while inhibiting T regulatory cells (1619). Multiple groups have subsequently reported that IMiDs directly bind cereblon (CRBN), a substrate adaptor of Cullin4 RING Ligase (CRL4) (20, 21) and activate CRL4CRBN ligase, thereby selectively targeting two B cell transcription factors IKAROS Family Zinc Finger 1 (IKZF1) and IKAROS Family Zinc Finger 3 (IKZF3) for ubiquitination and proteasomal degradation (22, 23). We have also shown that IMiDs directly bind and inhibit TP53-regulating kinase activity in MM cells, followed by MM cell growth inhibition (24). IMiDs trigger additive or synergistic anti-MM activity when combined with proteasome inhibitors and monoclonal Abs in preclinical models (25, 26) and are now used in combinations to treat both newly diagnosed and relapsed MM. However, development of resistance to IMiDs commonly underlies relapse of disease.

To delineate mechanisms of IMiD resistance, the majority of previous studies have focused on CRBN. The expression level of CRBN, CRBN-binding proteins, and CRL4CRBN ligase have been associated with IMiD sensitivity (2730). For example, our prior studies used CRISPR-Cas9 screening to identify signalosome genes regulating expression of CRBN and IMiD sensitivity (31). Although down-regulation or mutations in CRBN have been associated with IMiD resistance (32, 33), MM cells can manifest resistance without CRBN dysfunction (34), indicating potential alternative mechanisms of IMiD resistance. We and others have also shown that MM cell adhesion to extracellular matrix proteins and accessory cells triggers cell adhesionmediated drug resistance to conventional therapeutic agents (35, 36). Moreover, secretion of soluble factors [i.e., tumor necrosis factor (TNF-) and interleukin-6 (IL-6)] from celluar components [i.e., BM stromal cells (BMSCs), osteoclasts, and vascular endothelial cells] activates intracellular signaling pathways including nuclear factor B (NF-B), Rafmitogen-activated protein kinase (MAPK) kinase (MEK)extracellular signalregulated kinase (ERK), Janus kinasesignal transducer and activator of transcription, and phosphatidylinositol 3-kinaseAkt, thereby promoting migration, proliferation, survival, and drug resistance of MM cells (37). Resistance to dexamethasone-induced MM cell apoptosis, for example, is completely abrogated by coculture with BMSCs, IL-6, or insulin-like growth factor 1 (IGF-1). To date, however, the molecular mechanisms mediating IMiD resistance have not been fully delineated.

In this study, we used our in vitro and in vivo preclinical model systems of MM in the BM milieu to delineate molecular mechanisms underlying sensitivity to IMiDs. Genome-wide CRISPR-Cas9 knockout (KO) screening identified TRAF2, a member of TNF receptorassociated factor (TRAF) protein family, to regulate IMiD sensitivity. We show that TRAF2 KO-induced IMiD resistance is mediated via activation of noncanonical NF-B and downstream MEK-ERK signaling, independent of CRBN-IKZF1/3 axis. Within MM BMSC supernatants (SC-sup), TNF- induces proteasomal degradation of TRAF2, followed by noncanonical NF-B and downstream ERK signaling, whereas IL-6 directly triggers ERK activation. Combination MEK inhibitor treatment restores IMiD sensitivity of TRAF2 KO cells with high phosphorylated ERK (p-ERK) both in vitro in the presence of SC-sup and in vivo in an inducible TRAF2 knockdown (KD) MM xenograft model. These data, coupled with RNA sequencing (RNA-seq) showing enrichment of ERK signaling in patients with MM at the time of relapse while on single-agent Len maintenance therapy, provide the framework for clinical trials of MEK inhibitors to overcome IMiD resistance and improve patient outcome in MM.

We first carried out genome-wide CRISPR-Cas9 KO screening to identify genes and/or pathways mediating IMiD sensitivity (Fig. 1A and fig. S1, A and B). As expected, most of the positively selected genes are associated with activity of CRL4CRBN E3 ligase, the main target of IMiDs mediating their anti-MM activity. Among these genes, we have previously validated that COP9 signalosome complex regulates sensitivity to IMiDs by modulating CRBN expression (31). TRAF2 was identified in our top 10 genes list (Fig. 1A and fig. S1A), and we demonstrated that three different single-guide RNAs (sgRNAs) targeting TRAF2 were enriched after IMiD treatment (Fig. 1, B and C). To confirm that TRAF2 modulates IMiD sensitivity, we individually cloned the TRAF2 sgRNAs into the LentiCRISPRv2 vector (38) and reintroduced them into MM cells. As expected, TRAF2-KO MM cells acquired notable resistance to Pom and Len treatment (Fig. 1, D and E, and fig. S2, A to C). Conversely, IMiD-resistant RPMI 8226 MM cell line showed increased sensitivity to Pom when TRAF2 was overexpressed (fig. S2D). In patient samples, TRAF2 mRNA was expressed in samples from patients relapsing on Len [Dana-Farber Cancer Institute (DFCI)/Intergroupe Francophone du Myelome (IFM)] and on other therapies (CoMMpass database) (fig. S2E). However, TRAF2 immunohistochemical analysis of BM biopsies from six patients at the time of diagnosis with disease sensistive to Len compared to the time of relapse with disease resistant to single-agent Len maintenance demonstrated lower expression of TRAF2 protein in five of six samples at the time of relapse (Fig. 1F), suggesting that posttranslational modification of TRAF2 may account for clinical resistance. These data demonstrate that TRAF2 expression modulates sensitivity of MM cells to IMiDs.

(A) Volcano plot showing both positively and negatively selected genes in the CRISPR-Cas9 screen at day 21 after Pom treatment. Genes shown in red and blue represent positively and negatively selected genes, respectively. NS, not significant. (B) Normalized reads of sgTRAF2 from cells treated with either dimethyl sulfoxide (DMSO) control or Pom at the indicated time points. Veh, DMSO control. (C) Enrichment of TRAF2 and CRBN sgRNAs after Pom treatment. Each dot specifies one sgRNA. (D and E) Dose-dependent survival of Pom-treated (D) and Len-treated (E) MM.1S cells infected with individually cloned lentiCRISPR viruses targeting the selected gene candidates. Controls were null-targeting lentiCRISPR viruses. Error bars represent SEM (n = 3). IC50, half maximal inhibitory concentration. (F) Representative images of TRAF2 protein expression assessed by immunohistochemical staining of BM biopsies from six patients at time of diagnosis with disease sensitive to Len and at time of relapse with disease resistant to single-agent Len maintenance therapy. Scale bar, 20 M. (G) Representative Western blot analysis of control and TRAF2 KO MM.1S cells treated with DMSO, 0.5 M Pom, or 1 M Len for 72 hours. Whole-cell lysates (WCLs) were collected and probed with indicated Abs. GAPDH, glyceraldehyde-3-phosphate dehydrogenase; NT, non-targeting.

Because previous studies showed that CRBN-IKZF1/3 axis plays a crucial role in IMiD-induced MM cell growth inhibition, we next examined whether TRAF2 KO-induced IMiD resistance was CRL4CRBN ligase activity dependent. TRAF2 KO showed no effect on CRBN expression or IMiD-induced degradation of IKZF1/IKZF3 and down-regulation of interferon regulatory factor 4 (IRF4), the main effector of MM cell survival (Fig. 1G). Together, these data suggest that TRAF2 KOmediated IMiD resistance is independent of CRBN-IKZF1/3 axis.

We next investigated the molecular mechanism underlying IMiD resistance in TRAF2 KO cells. TRAF2 KO inhibited cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP) triggered by Pom and Len (Fig. 2, A and B, and fig. S3, A and B), indicating that TRAF2 KO inhibits apoptotic cell death triggered by IMiDs. We further confirmed that TRAF2 was required for IMiD-induced cytotoxicity using CellTiter-Glo Luminescent Cell Viability Assay (Fig. 2C and fig. S3C) and flow cytometric analysis with annexin V staining (fig. S3D). Notably, TRAF2 KO has no effect on MM cell growth and cell cycle (fig. S3, E and F). We also examined cross-resistance of TRAF2 KO cells to other therapeutic agents. Viability assays showed that TRAF2 KO cells were also resistant to dexamethasome and melphalan treatment (fig. S3G) but remained sensitive to bortezomib (BTZ) (fig. S3H). These data indicate that TRAF2 KOinduced drug resistance is not specific to IMiDs and independent of ubiquitin-proteasome pathway.

(A and B) Representative Western blot analyses of control and TRAF2 KO MM.1S cells treated with DMSO or 1 M Pom (A) or 1 M Len (B) for 72 hours. WCLs were collected and probed with indicated Abs. (C) Percentage cell viability of control and TRAF2 KO MM.1S cells treated with 0.5 M Pom for 72 hours. Cell viability was determined using CellTiter-Glo (CTG) cell viability assay. CRBN KO cells were analyzed as a positive control. Data are shown as means SEM. ***P < 0.001 by two-sided Students t test. (D) Gene set enrichment analysis plots of datasets identified comparing TRAF2 KO and wild-type signatures. NES, normalized enrichment score. FDR, false discovery rate. (E) Nuclear and cytoplasmic protein were extracted from MM.1S TRAF2 KO cells and immunoblotted with indicated Abs. Cyto, cytoplasmic; nuc, nuclear. (F) WCLs from control and TRAF2 KO MM.1S cells were probed for p-ERK, ERK, and TRAF2 by immunoblotting. The numbers under the bands of blots indicate band intensity normalized to control.

We next performed RNA-seq to delineate signaling cascades mediating IMiD resistance induced by TRAF2 KO. Both noncanonical NF-B (Fig. 2D, left) and ERK (Fig. 2D, right) pathways were enriched in TRAF2 KO cells, consistent with previous reports that TRAF2 regulates NF-B and ERK signaling pathways (39). TRAF2 KO cells showed significantly increased processing of precursor p100 to p52 (NFB2) (Fig. 2E and fig. S4A) and up-regulation of NF-Binducing kinase (NIK) (fig. S4B), as well as activation of noncanonical NF-B pathway (fig. S4C), with minimal impact on p105 or p50 (NFB1) protein expression (fig. S4D). These results suggest that TRAF2 KO predominantly activated noncanonical NF-B pathway. Consistent with RNA-seq analysis, we also confirmed that phosphorylation of ERK and upstream MEK were significantly up-regulated in TRAF2 KO MM cells (Fig. 2F and fig. S4, E to G).

Because both noncanonical NF-B and MEK-ERK pathways were activated in TRAF2 KO cells, we next examined interaction of these signaling pathways mediating IMiD resistance. p52 (NFB2) KO significantly reduced phosphorylation of MEK and ERK in TRAF2 KO cells (Fig. 3A), suggesting that noncanonical NF-B pathway may regulate MEK-ERK activity in TRAF2 KO cells. Moreover, p52 KO in TRAF2 KO cells resensitized them to IMiD treatment (Fig. 3, B and C, and fig. S4H). To further confirm the role of up-regulation of phosphorylated MEK-ERK in resistance to IMiDs, we overexpressed p-ERK2 in IMiD-sensitive MM.1S cells, which conferred resistance to IMiDs (Fig. 3D and fig. S4I). Together, these results indicate that TRAF2 KO activates noncanonical NF-B and downstream MEK-ERK signaling mediating IMiD resistance in MM cells.

(A) Representative Western blot analysis of control and KO MM.1S cells. WCLs were collected and probed with indicated Abs. (B) Percentage cell viability of sgTRAF2 and/or sgp52 MM.1S cells treated with 0.5 M Pom for 72 hours. Cell viability was determined using CTG assay. (C) KO efficiency of p100, p52, and TRAF2 in MM.1S cells was assessed by immunoblot analysis. (D) MM.1S cells were infected with lentivirus to constitutively express activated ERK2 and then treated with Pom (0 to 180 nM) for 72 hours. Cell viability was determined using CTG assay. Data in (B) and (D) are shown as means SEM. ***P < 0.001 by two-sided Students t test. OE, over-expressed; GFP, green fluorescent protein. (E and F) RNA-seq data from MM patient samples of 69 patients at first relapse on Len maintenance therapy. Enrichment scores for ERK pathway activation (E) and correlation between ERK and noncanonical NF-B pathway activation (F) were analyzed.

We next evaluated the clinical significance of ERK activation in relapsed MM patient samples. RNA-seq data from 69 MM patient samples demonstrated activated ERK pathway in 97% cases at the time of first relapse while receiving Len maintenance therapy (Fig. 3E). There was also a significant positive correlation between ERK and noncanonical NF-B signaling in relapsed MM patient samples (Fig. 3F and fig. S4J). These data suggest a pivotal role of ERK activity in mediating IMiD resistance in the clinical setting.

Because we confirmed that ERK activity mediates IMiD resistance, we next sought to determine whether blockade of ERK pathway can overcome IMiD resistance induced by TRAF2 KO. AZD6244 is a potent and highly selective MEK inhibitor (40), and we examined whether AZD6244 abrogated IMiD resistance in TRAF2 KO cells. We first showed that AZD6244 in combination with IMiDs triggered synergistic cytotoxicity in MM.1S wild-type (WT) cells, evidenced by inhibition of cell proliferation (fig. S5, A and B). Addition of AZD6244 overcame resistance and mediated synergistic cytotoxicity with IMiDs in TRAF2 KO MM cells, evidenced by decreased proliferation and p-ERK1/2, as well as by increased induction of PARP cleavage (Fig. 4, A and B, and fig. S5, C to E). To assess the efficacy of combination treatment in vivo, we first generated inducible TRAF2 KD MM.1S cells and confirmed that TRAF2 KD triggered activation of noncanonical NF-B and ERK pathways (fig. S5F) and Pom resistance (fig. S5G) in vitro. These cells were then subcutaneously injected into severe combined immunodeficient (SCID) mice, allowing for induction of TRAF2 KD by intraperitoneal injection of doxycycline. MM.1S WT cells were sensitive to Pom treatment, whereas MM.1S TRAF2 KD cells demonstrated resistance. The combination of AZD6244 and Pom significantly reduced in vivo tumor growth of TRAF2 KD cells, without associated host weight loss (Fig. 4, C to F). These data indicate that MEK inhibitor can abrogate activation of ERK1/2 and overcome IMiD resistance in vivo. Together, our results show that activation ERK signaling plays a crucial role modulating IMiD sensitivity and that MEK inhibitor can overcome ERK-mediated resistance and restore IMiD-induced MM cytotoxicity.

(A) Percentage cell growth of TRAF2 KO MM.1S cells after 3 days of treatment with Len (0 to 1 M) and ERK inhibitor AZD6244 (0 to 1 M). Cell growth was determined using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. (B) Representative Western blot analysis of TRAF2 KO MM.1S cells treated for 48 hours with AZD6244 (0 to 3 M), Len (0 to 3 M), or both. WCLs were collected and probed with PARP Ab. (C to F) MM.1S cells expressing doxycycline-induced shTRAF2 were injected subcutaneously into CB-17 SCID mice (n = 5 for each group). When tumors reached 100 mm3, mice were randomized and treated with vehicle, Pom (2.5 mg/kg), AZD6244 (12.5 mg/kg), or both drugs for 3 weeks. (C) Macroscopic photographs after 21 days of therapy. (Photo credit: Jiye Liu, DFCI). Tumor volume (D) and body weight (E) were monitored over the indicated time period. Data in (D) and (E) are shown as means SEM. **P < 0.01 by two-sided Students t test. (F) Representative images of TRAF2 and p-ERK1/2 immunohistochemistry stain in tumor tissue sections from each group. Scale bars, 40 M.

We and others have shown that the BM microenvironment plays an important role in promoting proliferation, survival, and drug resistance in MM cells (41). Specifically, we showed that either BMSCs or SC-sup activate NF-B and MEK-ERK pathways (37). We therefore next examined the relevance of TRAF2 KO-induced ERK activation-mediated IMiD resistance in the context of the BM microenvironment. As expected, coculture of MM cells with BMSCs (Fig. 5, A and B, and fig. S6, A and B) conferred resistance to IMiDs. Moreover, BMSC supernatants (SC-sup) similarly enhanced MM cell growth and conferred resistance to IMiDs (Fig. 5, C and D, and fig. S6C) associated with down-regulation of TRAF2 (Fig. 5E) and up-regulation of p-ERK (Fig. 5F). These data suggest that IMiD resistance in the BM microenvironment can be mediated, at least in part, by TRAF2 down-regulationinduced ERK activation.

(A and B) MM.1S cells were treated with indicated concentrations of Pom (A) or Len (B) in the presence or absence of BMSC. Cell growth was determined using MTT assay. (C) Percentage cell growth of MM.1S cells after 3 days culture with stromal cell supernatants (SC-sup). Cell growth (means SEM) was determined using MTT assay and normalized to medium control. SCs were from five patients with MM. (D) Percentage cell growth of MM.1S cells after 3 days of treatment with Pom (1 M), SC-sup, or both. Cell growth was determined using MTT assay and normalized to the DMSO control group. (E) Immunoblot analysis of TRAF2 protein level in MM.1S cells cultured with SC-sup for 48 hours. SCs were from five patients with MM. (F) MM.1S cells were cultured for 0 to 24 hours in the presence or absence of SC-sup. WCLs were collected and probed with p-ERK1/2 and ERK1/2 Abs. The numbers under the bands of blots indicate band intensity normalized to control. Data in (A) to (D) are shown as means SEM. ****P < 0.0001 and **P < 0.01 by two-sided Students t test.

To further delineate the mechanism whereby SC-sup confers IMiD resistance, we next performed cytokine array analysis and identified that TNF- and IL-6 were highly secreted by BMSCs (Fig. 6A). TNF-, but not IL-6, treatment induced TRAF2 down-regulation in MM cell lines (Fig. 6, B and C) and patient MM cells (Fig. 6D). TNF- significantly inhibited IMiD-induced MM cytotoxicity in a dose-dependent manner (Fig. 6E and fig. S7, A to C), and similar to TRAF2 KO, TNF- induced IMiD resistance by activating ERK and noncanonical NF-B pathways (fig. S7, D and E), without altering CRBN expression (fig. S7F).

(A) Representative image of cytokine Ab array screening of SC-sup. Supernatant was collected after 24-hour culture with BMSCs and filtered by a 0.22 M low-protein binding membrane. (B) Representative Western blot analysis of MM.1S cells treated with TNF- or IL-6 for 24 hours. WCLs were collected and probed with TRAF2 Ab. (C) MM cell lines were treated with TNF- (5 ng/ml) for 48 hours. Cell lysates were collected and blotted with TRAF2 Ab. (D) Immunoblot analysis of patient MM cells treated with TNF- (5 ng/ml) for 48 hours. WCL was collected and probed with TRAF2 Ab. (E) Percentage cell growth of MM.1S cells after 5 days of treatment with Pom (0 to 3 M) and/or TNF- (0 to 3 ng/ml). Cell growth (means SEM) was determined using MTT assay. (F) MM.1S cells were treated with TNF- (5 ng/ml) for 0 to 10 hours. WCLs were collected and probed with TRAF2 Ab. (G) MM.1S cells were treated with 0.5 nM BTZ or 2.5 nM CFZ for 2 hours, followed by treatment with TNF- (10 ng/ml) for 24 hours. WCLs were collected and probed with TRAF2 Ab. (H) MM.1S cells were cultured with TNF- (5 ng/ml) for 18 hours and then treated with MG132 (10 M) for 6 hours. WCLs were collected and immunoprecipitated by anti-TRAF2 Ab and probed for polyubiquitinated protein and TRAF2. IP, immunoprecipitated. The numbers under the bands of blots indicate band intensity normalized to control.

To further define the mechanism of TNF-mediated TRAF2 down-regulation, we next showed that TNF- promoted TRAF2 protein degradation in a time- and dose-dependent manner (Fig. 6F and fig. S8A) and that the half-life of TRAF2 was markedly shortened by TNF- treatment (fig. S8B). Because previous studies identified TRAF2 as a substrate of the proteasome (42), we also treated MM cells with TNF- in the presence or absence of proteasome inhibitor BTZ or carfilzomib (CFZ). Notably, TRAF2 down-regulation triggered by TNF- was inhibited by these proteasome inhibitors (Fig. 6G), associated with accumulation of ubiquitinated TRAF2 (Fig. 6H). These data confirm that TNF-induced TRAF2 down-regulation is due, at least in part, to its proteasomal degradation in MM cells. As described above, TRAF2 KO induced MEK-ERK phosphorylation via noncanonical NF-B activation, resulting in IMiD resistance. Consistent with a previous study (43), we also show that TNF- also triggered ERK phosphorylation (fig. S7D). Last, we and others have shown that IL-6 activates ERK signaling and resistance to dexamethasone-induced MM cell apoptosis (44). Here, we show that IL-6 also directly induces IMiD resistance (Fig. 7A). In contrast, IGF-1 does not trigger ERK activation or IMiD resistance (fig. S9). These data therefore indicate that soluble factors which induce MEK-ERK activation can protect MM cells from IMiD-induced cytotoxicity in the BM microenvironment.

(A) Percentage cell growth of MM.1S cells after 5 days of treatment with Len (0 to 3 M) and/or IL-6 (0 to 10 ng/ml). Cell growth (means SEM) was determined using MTT assay. (B) Representative Western blot analysis of MM.1S cells cultured for 72 hours in the presence of BMCS with AZD6244 (1 M), Len (1 M), or both. WCLs were collected and probed with anti-cleaved PARP, IKZF1, p-ERK, and ERK Abs. (C) Percentage MM.1S cell growth in cultures with or without SC-sup after 5 days of treatment with Pom (0 to 1 M), AZD6244 (0 to 1 M), or both. Cell growth (means SEM) was determined using MTT assay. (D) Percentage MM.1S cell growth in cultures with IL-6 (5 ng/ml) after 5 days of treatment with Pom (0 to 1 M), AZD6244 (0 to 1 M), or both. Cell growth (means SEM) was determined using CTG assay. (E) Percentage MM.1S cell growth in cultures with TNF- (5 ng/ml) after 5 days of treatment with Pom (0 to 1 M), AZD6244 (0 to 1 M), or both. Cell growth (means SEM) was determined using CTG assay.

Because SC-sup (Fig. 5F), TNF- (fig. S7D), and IL-6 (Fig. 7A) induced ERK phosphorylation and IMiD resistance in MM cells, we next determined whether MEK inhibitor was able to inhibit ERK1/2 phosphorylation and overcome IMiD resistance in the context of the BM microenvironment. We first showed that SC-supinduced phosphorylation of ERK was completely blocked by a MEK inhibitor, AZD6244 (Fig. 7B). Moreover, PARP cleavage was markedly enhanced by combination treatment of Pom with AZD6244, without affecting IKZF1 degradation (Fig. 7B). Addition of AZD6244 overcame resistance to Pom and Len in SC-suptreated MM cells (Fig. 7C and fig. S10, A and B). We also observed that IMiD resistance triggered by IL-6 or TNF- was similarly abrogated by AZD6244 (Fig. 7, D and E). These data indicate that MEK-ERK inhibitor can overcome IMiD resistance triggered by TNF- and IL-6 in SC-sup and restore MM cell sensitivity to IMiD treatment in the BM millieu.

During the past two decades, IMiDs have demonstrated remarkable anti-MM activity when used alone or combined with proteasome inhibitors and/or monoclonal Abs as initial, salvage, and maintenance therapies (7, 25, 26, 45, 46). More potent IMiDs with enhanced affinity to CRBN have recently been developed to even further increase their clinical efficacy (4749). Moreover, we and others (24) have also identified novel binding protein of IMiDs, such as TP53-regulating kinase, which may broaden their clinical utility. However, most MM cells eventually acquire resistance to IMiDs, which has, to date, been attributed to decreased expression of CRBN and rarely CRBN mutations (50, 51). Defining mechanisms underlying clinical resistance to IMiDs is therefore essential to inform the design of novel strategies to restore and/or enhance IMiD sensistivity and improve patient outcome.

Targeted genome editing technologies have transformed our abilities to discover basic biological mechanisms underlying specific phenotypes (52, 53). Specifically, the development of the CRISPR-Cas9 system and Cas9-based functional genetic screening tools has facilitated the identification of genes essential for drug resistance (54, 55), and we have used genome-wide CRISPR-Cas9 KO screening to delineate mechanisms of IMiD resistance in MM. We found that many CRL4CRBN E3 ubiquitin ligaseassociated genes are enriched in positively selected genes, confirming that CRBN pathway genes mediate sensitivity of MM to IMiDs. Conversely, many genes essential for MM survival and proliferation (31, 5658) are depleted in negatively selected genes. From this screening, we previously identified the signalosome (CSN) family genes to be positively enriched, and validated that CSN genes regulate CRBN expression, suggesting that strategies to up-regulate CSN may restore CRBN levels and IMiD sensitivity (31). In the current study, we identified TRAF2 as one of the top 10 genes positively selected in our genome-wide CRISPR-Cas9 KO screening. TRAF2 is a member of the TRAF protein family functions as a component of TNF receptor complex and mediates activation of NF-B and/or ERK pathways (59, 60). It also functions as a RING domain E3 ligase that is activated by sphingosine-1-phosphate and catalyzes the lysine-63linked polyuniquitination of receptor interacting serine/threonine kinase 1 (RIP1), thereby leading to NF-B activation (61).

An integrated analysis from 155 MM samples identified that inactive mutations of TRAF2 result in constitutive activation of noncanonical NF-B pathway (62). Here, we show that TRAF2 KO significantly induces IMiD resistance, thereby identifying TRAF2 as an essential mediator of IMiD sensitivity in MM cells. However, TRAF2 KO does not alter CRBN expression or IMiD-induced degradation of IKZF1/3 and its downstream targets IRF4 and c-Myc. Our data therefore identify a novel mechanism underlying IMiD resistance, independent of the CRBN-IZKF1/3 axis. We show that IMiD resistance in TRAF2 KO cells is mediated by noncanonical NF-B and its downstream ERK signaling and that MEK inhibitor AZD6244 can restore sensitivity to IMiDs in vitro and in vivo using our inducible TRAF2 KD MM model. This is of great potential clinical interest, because our analyses of RNA-seq data show nearly universal activation of ERK signaling in MM patient samples at the time of first relapse while on Len maintenance therapy, suggesting that ERK inhibitor may restore IMiD sensitivity in the clinic.

We and others have shown that BMSCs and accessory cells (plasmacytoid dendritic cells, myeloid-derived suppressor cells, osteoclasts, and T regulatory cells) in the MM BM microenvironment play a crucial role in MM pathogenesis by promoting tumor cell growth, survival, and immunosuppression, as well as conferring drug resistance. These biologic sequelae are due to direct tumor cellBMSC/accessory cell interaction (35) and/or secretion of soluble factors including IL-6, TNF-, IGF-1, and vascular endothelial growth factor (63, 64) in the BM milieu. Moreover, our early studies showed that TNF- can directly stimulate the production of IL-6 and up-regulate adhesion molecules (65), thereby further promoting tumor/accessory cell interactions. Here, we show that SC-sup, IL-6, and TNF- induce IMiD resistance in MM cells mediated via ERK signaling. Although IL-6 directly activates ERK signaling, we show that TNF- triggers proteasomal degradation of TRAF2 and activation of noncanonical NF-B, with downstream ERK pathway activation. In contrast, IGF-1 neither activates ERK signaling nor triggers IMiD resistance. Therefore, ERK pathway signaling is implicated in mediating IMiD resistance triggered by multiple stimuli in the BM milieu. Combination MEK inhibitor AZD6244 with IMiDs overcomes resistance to Pom and Len conferred by the BM milieu.

In summary, we have identified and validated that activation of MEK-ERK pathway directly by soluble factors (i.e., IL-6) or indirectly by activation of TRAF2 degradationinduced noncanonical NF-B activation mediates IMiD resistance in the BM microenvironment. These studies not only delineate a novel CRBN-independent mechanism of IMiD resistance in the BM milieu but also provide the preclinical rationale for combining inhibitors of MEK/ERK signaling with Len or Pom to overcome IMiD resistance and improve patient outcome in MM.

MM.1S, RPMI 8226, H929, U266, and human embryonic kidney (HEK) 293T cells were purchased from the American Type Culture Collection. AMO-1, JJN-3, OPM2, and KMS-12BM cells were purchased from Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ). All cell lines were verified by short tandem repeat (STR) DNA fingerprinting analysis (Molecular Diagnostic Laboratory, DFCI) and tested for mycoplasma using the MycoAlert Mycoplasma Detection Kit (Lonza). All cells were grown at 37C in 5% CO2 condition: MM.1S, RPMI 8226, H929, U266, AMO-1, JJN-3, OPM2, and KMS-12BM cells were maintained in RPMI 1640 medium; HEK293T cells were maintained in Dulbeccos modified Eagles medium. All media were supplemented with 10% fetal bovine serum (FBS), 1 antibiotic-antimycotic, 1 GlutaMAX, and 1 Hepes.

BM samples were obtained from patients with MM after informed consent and approval by the Institutional Review Board of the DFCI. Mononuclear cells were separated by Ficoll-Paque PLUS (GE Healthcare Life Sciences). MM cells were purified by CD138-positive selection with human CD138 MicroBeads (Miltenyi). Long-term BMSCs were established by culturing CD138-negative BM mononuclear cells for 4 to 6 weeks in RPMI 1640 medium supplemented with 10% FBS and 1 antibiotic-antimycotic.

The culture medium of established BMSCs was replaced with fresh complete medium. Supernatant was collected 24 hours later, followed by centrifugation at 2000 rpm for 10 min to clear cells and debris. Filtration was then performed with a 0.22 M low-protein binding membrane (Millipore Sigma).

Len, Pom, BTZ, CFZ, and MG132 were purchased from Selleck Chemicals; AZD6244 was purchased from Cayman Chemical. All were dissolved in dimethyl sulfoxide (DMSO) and stored at 20C for up to 6 months. For all cell-based experiments, drugs were diluted at least by 1:1000 to ensure that the final DMSO concentration was lower than 0.1%. Cycloheximide solution was purchased from Millipore Sigma. Human recombinant TNF- and IL-6 were purchased from STEMCELL Technologies. Doxycycline was purchased from Boston Bioproducts. Abs were obtained as follows: IKZF1 (no. 5443, Cell Signaling Technology), IKZF3 (no. 15103, Cell Signaling Technology), IRF4 (no. 4299, Cell Signaling Technology), CRBN (no. SAB045910, Sigma-Aldrich), TRAF2 (no. 4724, Cell Signaling Technology and no. ab126758, Abcam), glyceraldehyde-3-phosphate dehydrogenase (no. 5174, Cell Signaling Technology), cleaved PARP (no. 5625, Cell Signaling Technology), caspase-3 (no. 14220, Cell Signaling Technology), NF-B2 p100/p52 (no. 4882, Cell Signaling Technology), histone H3 (no. 4499, Cell Signaling Technology), phosphoNF-B2 p100 (Ser866/870) (no. 4810, Cell Signaling Technology), ubiquitin (no. 3936, Cell Signaling Technology), p44/42 MAPK (Erk1/2) (no. 4695, Cell Signaling Technology), phosphor-p44/42 MAPK (Erk1/2) (Thr202/Tyr204) (no. 4370, Cell Signaling Technology), pan-actin (no. 8456, Cell Signaling Technology), NF-B1 p105/p50 (no. 3035, Cell Signaling Technology), lamin A/C (no. 4777, Cell Signaling Technology), anti-rabbit immunoglobulin G (IgG), horseradish peroxidase (HRP)linked Ab (no. 7074, Cell Signaling Technology), and anti-mouse IgG, HRP-linked Ab (no. 7076, Cell Signaling Technology). Protein G Sepharose was purchased from Millipore Sigma.

For RNA-seq, total RNA of WT and TRAF2 KO cells was extracted using the RNeasy Mini Kit (Qiagen). Library was prepared, and samples were sequenced on NovaSeq 6000 PE150. RNA-seq datasets were aligned to human reference genome hg38 using Homo sapiens steroidogenic acute regulatory protein (STAR). RNA-seq by expectation-maximization was used to do the transcript quantification, and differential expression analysis was performed with DESeq2. Gene set enrichment analysis (GSEA) was performed to identify significantly enriched pathways. The biologically defined gene sets were obtained from the Molecular Signatures Database (http://software.broadinstitute.org/gsea/msigdb/index.jsp). Genes used for GSEA analysis were preranked on the basis of log2 fold change of TPM (transcripts per kilobase million) between WT and TRAF2 KO cells.

Cells were plated in medium (8000 cells per well, 100-l final volume) in white, 96-well opaque plates (no. 3917, Corning). Cells were incubated for indicated intervals at 37C in a 5% CO2 incubator. Assay plates were removed from the incubator and equilibrated to room temperature before addition of 50 l of CellTiter-Glo reagent (Promega), according to the manufacturers instructions. Plates were shaken on an orbital shaker for 2 min at 500 rpm and then incubated at room temperature on the bench top for at least 10 min. Luminescence was detected using a spectrophotometer (SpectraMax M3, Molecular Devices).

The growth-inhibitory effect was assessed by measuring 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) (Sigma-Aldrich) dye absorbance, as previously described (56). Cells were cultured in 96-well plates (100 l) with or without drug treatment; for the last 4 hours, cells were pulsed with 10 l of MTT, followed by addition of 100 l of isopropanol containing 0.04 N HCl. Absorbance was measured at 570 nm, with 630 nm as a reference wavelength, using a spectrophotometer (SpectraMax M3, Molecular Devices).

Cells were treated, harvested, washed with phosphate-buffered saline, and lysed in radioimmunoprecipitation assay buffer (no. R0278, Millipore Sigma) containing protease inhibitor and phosphatase inhibitor (no. 78440, Thermo Fisher Scientific). The suspension was incubated for 15 min on ice and vortexed for 5 min. Then, samples were centrifuged at 13,000 rpm at 4C for 10 min. The supernatant was used as whole-cell lysates. Protein concentrations were quantified with a BCA protein assay kit (no. 23227, Thermo Fisher Scientific). Samples were mixed with 4 LDS sample buffer (no. NP0007, Thermo Fisher Scientific), and boiled at 95C for 8 min. Equal amounts of protein were run on NuPAGE Bis-Tris gels (Thermo Fisher Scientific) at a constant voltage. Proteins were transferred onto nitrocellulose membrane by iBlot Gel Transfer Device (Thermo Fisher Scientific). Then, the membranes were blocked in 5% nonfat dry milk for 1 hour at room temperature and incubated with primary Abs in 5% bovine serum albumin at 4C overnight. Blots were then washed three times with 1 Tris Buffered Saline with Tween (TBS-T), before incubation with secondary Abs for 1 hour. SuperSignal chemiluminescent substrate (Thermo Fisher Scientific) was used for signal detection. For reblotting the membranes, blots were stripped in stripping buffer (no. 46428, Thermo Fisher Scientific) according to the manufacturers instruction and reblocked. The intensity of band was quantified by ImageStudio (LI-COR).

On day 0, HEK293T cells were plated in a T150 flask. On day 1, for each flask, 20 g of lentiviral vector, 15 g of psPAX2 (no. 12260, Addgene), and 10 g of pMD2.G (no. 12259, Addgene) diluted in 3 ml of Opti-MEM were combined with 150 l of Lipofectamine 2000 diluted in 3 ml of Opti-MEM. The mixture was left for 20 min and then added to the cells. Twelve hours after transfection, the medium was replaced by fresh complete medium. The supernatant containing virus was collected 72 hours after transfection, followed by centrifugation at 2000 rpm for 10 min to pellet cell debris. Filtration was then performed with a 0.45-m low-protein binding membrane (no. SE1M003M00, Millipore). Then, the virus was concentrated by the Lenti-X Concentrator (no. 631231, Takara).

For generation of CRISPR KO cell lines, oligonucleotides (table S1) targeting different genes were annealed and subcloned into LentiCRISPRv2 vectors (38). Constructs were packaged into lentivirus in HEK293T cells. Target cells were seeded in 12-well plates and spinfected with virus for 1.5 hours at 2000 rpm at 35C, supplemented with Polybrene (8 g/ml). Medium was then aspirated, and fresh complete medium was added to exclude Polybrene. After 1 day, cells were selected for stable KO using puromycin (0.5 g/ml). After 7 days, cells were collected for immunoblotting or other experiments. To generate inducible TRAF2 KD cells for in vivo study, the SMARTvector inducible human TRAF2 lentivirus plasmid (Horizon Dharmacon) was transfected into HEK293T cells with packaging vectors. Cells were spinfected for 1 hour with viral particles at 2000 rpm at 35C, supplemented with Polybrene (8 g/ml). After 1 day, cells were selected with puromycin (0.5 g/ml) for 7 days. For the constitutive expression of ERK2-MEK1 fusion protein, the sequence of full length of ERK2-MEK1 was cloned from pCMV-myc-ERK2-L4A-MEK1_fusion vector (no. 39197, Addgene) into plenti-CMV-Puro-DEST (no. 17452, Addgene). The expression plasmid was transfected into HEK293T cells with the packaging vectors. Cells were spinfected for 1.5 hours with viral particles at 2000 rpm at 35C, supplemented with Polybrene (8 g/ml). After 1 day, cells were selected with puromycin (0.5 g/ml) for 7 days.

The cytokine array assay was performed using a Human Cytokine Array C5 kit (no. AAH-CYT-5-2, RayBiotech), according to the manufacturers instruction.

MM cells were treated with TNF- (5 ng/ml) for 24 hours and then 10 M MG132 for 6 hours. Cells were lysed in IP lysis buffer (no. 87787, Thermo Fisher Scientific). TRAF2 protein was pulled down by Protein G Agarose with TRAF2 Ab overnight at 4C and washed with IP lysis buffer. Protein was eluted by incubation with LDS loading buffer at 100C for 5 min, separated by SDSpolyacrylamide gel electrophoresis, transferred to nitrocellulose membrane, and probed with indicated Abs.

Cells were cultured in 12-well plates with or without TNF- and treated with cycloheximide (100 g/ml) for the indicated time periods before harvest. Cell lysates were analyzed by Western blotting.

A total of 6 106 Tet-inducible TRAF2 KD MM.1S cells were suspended in 100 l of RPMI 1640 medium and injected into the flanks of 200 cGyirradiated female SCID mice. Tumor size was measured every 2 days with an electrical caliper. The tumor volume was determined with the formula: (length width2) 0.5, where length is the longest diameter and width is the shortest diameter. When the tumor volume reached 100 to 150 mm3, xenografted mice were randomized to treatment and control cohorts. In the TRAF2 KD group, mice received doxycycline (2.5 mg/kg) via intraperitoneal injection to induce TRAF2 KD. AZD6244 (12.5 mg/kg per day) and Pom (2.5 mg/kg for 5 days/week) administrated by oral gavage. All care and treatment of experimental animals was conducted under a protocol approved by DFCI Institutional Animal Care and Use Committee guidelines. All mice were housed in a pathogen-free environment at a DFCI animal facility and were handled in strict accordance with Good Animal Practice, as defined by the Office of Laboratory Animal Welfare.

Cells were harvested and concentrations adjusted to 1 106 cells/ml. After washing, cells were suspended in 50 l of Hanks balanced salt solution (HBSS) containing 2% FBS; 1 ml of ice-cold 70% ethanol was then added in a dropwise manner while mixing gently on a vortex, with storage on ice for no less than 2 hours. Pelleted cells were washed with HBSS containing 2% FBS twice, and then 1 ml of 4,6-diamidino-2-phenylindole (DAPI) working solution was added, followed by incubation in the dark for 15 to 30 min at room temperature. Cells were filtered through a 40-m mesh filter and then analyzed by flow cytometry.

MM cells (1 106) were treated with Pom for 5 days and then stained with the LIVE/DEAD Fixable Aqua Dead Cell Staining Kit (no. L34957, Thermo Fisher Scientific) and annexin Vphycoerythrin conjugate (no. 640908, BioLegend), according to the manufacturers instruction. Cells were analyzed in BD FACSCanto II (BD Biosciences) using the FACSDiva software (BD Biosciences).

Tissue specimen sections of formalin-fixed, paraffin-embedded BM biopsies from six patients at diagnosis with MM sensitive to Len and at the time of relapse with disease resistant to single-agent Len were prepared and precessed for immunohistochemistry to detect TRAF2 protein expression by using TRAF2 Ab (no. ab126758, Abcam). Tumor samples from mice were harvested and fixed in formalin and then embedded in paraffin and cut in 4 M sections. Sections were stained with TRAF2, p-ERK1/2, and DAPI. Tissues were imaged using a microscope.

RNA-seq data from 69 patients with MM at the time of first relapse while on single-agent Len maintenance (DFCI/IFM) were collected after study participants provided written informed consent. After RNA extraction, RNA quantity was evaluated, and only samples with 100 ng of RNA with RNA integrity number (RIN) value 7 were sequenced with stranded 50base pair paired-end sequencing. After quality control, raw samples were quantified using Salmon and Gencode transcripts. Single-sample GSEA (ssGSEA), an extension of GSEA, was used to calculate separate enrichment scores for ERK pathway. R and ggpubr were used for statistical test and visualization. Pearson correlation analysis and Fishers exact test were used for association analysis and enrichment in relapse samples. The DFCI/IFM and CoMMpass patient sample RNA-seq databases were used to analyze correlation between noncanonical NF-B and ERK pathway activation in relapsed patient samples. TPM-level gene expression data were used only for patients who had CD138+ BM samples profiled at the time of relapse. We downloaded the Biocarta ERK pathway and Gene Ontology NIK NF-B signaling pathways from the Molecular Signatures Database website, and with ssGSEA, we quantified the enrichment score for each patient. Spearman correlation between the two pathways were evaluated using R and ggpubr.

Students t test or analysis of variance followed by Dunnetts test was used to compare differences between the treated group and the relevant control group. A value of P < 0.05 was considered significant.

Acknowledgments: We thank E. Campeau, M. Robinson, and F. Zhang for expression vectors. We also thank D. Chauhan and E. Morelli for helpful comments. We thank the staff from the hematologic neoplasia core facilities at DFCI for technical assistance. We also thank the Genome Center of WuXi AppTec Inc. for the initial data analysis of the CRISPR screening. Funding: This work was supported by the National Institutes of Health grants SPORE-P50100707 (to K.C.A.), R01-CA050947 (to K.C.A.), R01-CA178264 (to T.H. and K.C.A.), and P01-155258 (K.C.A. and N.M.). K.C.A. is an American Cancer Society Clinical Research Professor. This study was also supported, in part, by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Riney Family Myeloma Initiative, and the National Natural Science Foundation of China (NSFC grant no. 81800204). Author contributions: K.C.A. conceived the project, designed the research, analyzed the data, wrote the manuscript, and supervised the project. J.L. and T.H. designed and performed the research, analyzed data, and wrote the manuscript. J.L. and L.X. performed xenograft experiments. S.W. and W.Z. performed CRISPR-Cas9 screening data analysis. M.K.S. analyzed RNA-seq data from patients with MM. T.S. performed immunohistochemistry. D.O. provided assistance in some cell-based assays. G.A. and G.B. provided BM sections. S.G. and L.Y. performed immunohistochemistry. T.J. performed some Western blot experiments. K.W. helped process the human samples. R.C. provided biological materials and performed immunohistochemistry. Y.-T.T. provided biological material and analyzed data. N.M. and P.R. helped collect patient samples and analyzed data. Y.C. helped analyze data and revised the manuscript. Competing interests: K.C.A. serves on advisory boards to Millennium, Janssen, Sanofi, Bristol Myers Squibb, Gilead, Precision Biosciences, and Tolero and is a scientific founder of OncoPep and C4 Therapeutics. The authors declare that they have no other competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. All sequencing data were uploaded to Gene Expression Omnibus with accession no. GSE171341.

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ERK signaling mediates resistance to immunomodulatory drugs in the bone marrow microenvironment - Science Advances

Lymph nodes are small, bean-shaped glands that play a crucial role in the immune system. They filter lymphatic fluid, which helps rid the body of germs and remove waste products.

The body contains hundreds of lymph nodes. They form clusters around the body and are particularly prominent in areas such as the neck, armpit and groin and behind the ears.

The bodys cells and tissues dispose of waste products in lymphatic fluid, which lymph nodes then filter. During this process, they catch bacteria and viruses that could harm the rest of the body.

Lymph nodes are an essential part of the bodys immune system. Due to their function, they come into contact with toxins, which can cause them to swell. Although swollen lymph nodes are common, they may occasionally indicate lymph node cancer, or lymphoma.

Keep on reading to learn more about lymph nodes and their function within the immune system.

Lymph nodes are part of the lymphatic system, which is a complex network of nodes and vessels.

In certain areas of the body, such as the neck, armpit, and groin, lymph nodes sit close to the skin. This means a person may feel them swell when an infection develops.

Lymph nodes are also present in the stomach and between the lungs. However, there are no lymph nodes in the brain or spinal cord.

The name of a lymph node depends on its location in the body.

Lymph nodes form clusters throughout the body. Their main function is to filter out potentially harmful substances.

All tissues and cells in the body excrete lymphatic fluid, or lymph, in order to eliminate waste products. The lymph then travels through vessels in the lymphatic system and passes through lymph nodes for filtering.

Lymph nodes contain lymphocytes. These are a type of white blood cells that help destroy pathogens, such as bacteria, viruses, and fungi. When lymph nodes detect a pathogen in the lymph, they produce more lymphocytes, which causes them to swell.

Upon encountering bacteria or damaged cells, lymph nodes destroy them and turn them into a waste product.

When the lymph reenters the bloodstream, waste products travel to the kidneys and liver. The body then excretes waste products in the urine and feces.

Learn more about how the lymphatic system works here.

Swollen lymph nodes do not always indicate cancer. Below, we list some of many conditions that can cause lymph node swelling.

Lymphadenitis occurs when bacteria, viruses, or fungi in the lymph infect lymph nodes. When this happens, lymph nodes swell and are painful to the touch.

If multiple clusters of nodes become infected, a person may feel pain and swelling in both their neck and groin.

The most common type of lymphadenitis is localized lymphadenitis. This means the condition only affects a few nodes. If the infection occurs in several node clusters, a doctor will likely diagnose generalized lymphadenitis.

The condition usually results from an infection elsewhere in the body.

Symptoms of lymphadenitis include:

Lymphadenitis treatments include:

The type of treatment necessary will depend on a variety of factors, such as the severity of the disease and a persons underlying conditions and allergies. A doctor will help a person choose the most suitable treatment based on these factors.

Learn more about swollen lymph nodes in the neck here.

Swollen lymph nodes in the neck may be due to a viral or bacterial throat infection, such as strep throat.

Viral throat infections, such as colds, can present with swollen lymph nodes, a runny nose, and pinkeye.

These infections usually resolve on their own. However, a person can take over-the-counter pain relievers to alleviate pain they may experience when swallowing.

Strep throat is a bacterial infection that develops in the throat and tonsils due to group A streptococcus. People may contract strep throat if they come into contact with droplets containing the strep bacteria.

A person with strep throat may experience swollen lymph nodes on the neck, a sore throat, a fever, and red spots on the roof of the mouth.

Doctors treat strep throat with antibiotics.

Impetigo is an infection that develops due to group A streptococcus and may cause lymph nodes in the armpits and groin to swell.

A person can contract impetigo when the bacteria enter the body through a break in the skin. This can happen through sharing a towel, razor, or yoga mat.

Symptoms of impetigo include:

If a person has impetigo, they should seek medical attention to address their symptoms and prevent the condition from spreading to others.

Treatment will usually involve antibiotics.

Ringworm, or jock itch, is a fungal infection that can affect many areas of the body. If the fungus develops in the groin, a person may experience lymph node swelling in that area.

Typically, ringworm starts as a fungal lesion. The fungus often transmits when people share towels or razors.

Ringworm thrives in moist environments, and therefore a person should take care to dry thoroughly after a wash and try not to stay in damp clothes.

Common ringworm symptoms include:

A doctor will prescribe an antifungal treatment to address ringworm.

The best way to prevent ringworm is to wear breathable fabrics, avoid sharing towels and razors, and dry thoroughly after bathing.

Learn more about swollen lymph nodes in the groin here.

Lymphoma is a type of cancer that affects the lymphatic system. The two main types of lymphoma are Hodgkin lymphoma and non-Hodgkin lymphoma.

Hodgkin lymphoma occurs when cancer cells spread from one cluster of lymph nodes to another. By contrast, in non-Hodgkin lymphoma, there is no order in how cancer cells spread throughout the lymphatic system.

Typical symptoms of lymphoma include:

These are also common symptoms of viral infections, which can make lymphoma hard to diagnose. However, in people with lymphoma, symptoms tend to persist for longer periods of time.

It is of note that these symptoms do not clearly indicate cancer. If a person experiences any of these, they should contact a doctor to identify the cause of their symptoms.

Treatment options for lymphoma include:

A person should contact a healthcare professional if they are experiencing persistent swelling of lymph nodes.

Swelling usually indicates an infection, and therefore a person should not immediately worry about lymphoma.

After reaching a diagnosis, a doctor will recommend the appropriate course of treatment.

Lymph nodes are a part of the lymphatic system. They filter lymph, which contains pathogens and damaged cells, and send the dead cells to the kidneys and liver.

Lymph node swelling usually results from an infection. In rare cases, however, it may be due to lymphoma.

If a person is concerned about swelling and other symptoms they have, they should contact a doctor.

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Lymph nodes: Purpose, location, and disease warning signs - Medical News Today

DUBLIN--(BUSINESS WIRE)--The "Global Stem Cell Therapy Market by Type (Allogeneic, Autologous), Therapeutic Application (Musculoskeletal, Wound & Injury, CVD, Autoimmune & Inflammatory), Cell Source (Adipose tissue, Bone Marrow, Placenta/Umbilical Cord) - Forecasts to 2026" report has been added to ResearchAndMarkets.com's offering.

The global stem cell therapy market is projected to reach USD 401 million by 2026 from USD 187 million in 2021, at a CAGR of 16.5% during the forecast period.

Growth in this market is majorly driven by the increasing investment in stem cell research and the rising number of GMP-certified stem cell manufacturing plants. However, factors such as ethical concerns and the high cost of stem cell research and manufacturing process likely to hinder the growth of this market.

The allogeneic stem cell therapy segment accounted for the highest growth rate in the stem cell therapy market, by type, during the forecast period

The stem cell therapy market is segmented into allogeneic and autologous stem cell therapy. Allogeneic stem therapy segment accounted for the largest share of the stem cell therapy market. The large share of this segment can be attributed to the lesser complexities involved in manufacturing allogeneic-based therapies.

This segment is also expected to grow at the highest growth rate due to the increasing number of clinical trials in manufacturing allogeneic-based products.

Bone Marrow-derived MSCs segment accounted for the highest CAGR

Based on the cell source from which stem cells are obtained, the global stem cell therapy market is segmented into four sources. These include adipose tissue-derived MSCs (mesenchymal stem cells), bone marrow-derived MSCs, placenta/umbilical cord-derived MSCs, and other cell sources (which include human corneal epithelium stem cells, peripheral arterial-derived stem cells, and induced pluripotent stem cell lines).

The bone marrow-derived MSCs segment is expected to witness the highest growth rate during the forecast period, owing to an increasing number of clinical trials focused on bone marrow-derived cell therapies and the rising demand for these cells in blood-related disorders.

Asia Pacific: The fastest-growing country in the stem cell therapy market

The stem cell therapy market is segmented into North America, Europe, Asia Pacific, RoW. The stem cell therapy market in the Asia Pacific region is expected to grow at the highest CAGR during the forecast period.

Factors such as the growing adoption of stem cell-based treatment in the region and the growing approval & commercialization of stem cell-based products for degenerative disorders drive the growth of the stem cell therapy market in the region.

Market Dynamics

Drivers

Restraints

Opportunities

Challenges

Companies Mentioned

For more information about this report visit https://www.researchandmarkets.com/r/qiagh1

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Stem Cell Therapy Market by Type, Therapeutic Application and Cell Source - Global Forecasts to 2026 - ResearchAndMarkets.com - Business Wire

When he called the Olivia Hospital and Clinic to postpone his physical, he was urged to keep it. Physicals are important, he was reminded.

Keeping that date proved to be a lifesaving decision.

The physical went well, and shortly after he told his daughter that he was as fit as a horse.

But Dr. Jon Kemp, his primary physician who had urged him to keep the date for the physical, noticed a slight abnormality in a standard blood test. He recommended further testing.

On Dec. 20 Kramer was diagnosed with multiple myeloma.

Thanks to the early diagnosis, Kramer, age 62, has the means of keeping this disease at bay. Its a cancer of the plasma cells in bone marrow, and is the second most common blood cancer.

He is about to undergo a stem cell transplant this week as part of his treatment.

He learned that hes not alone on the journey ahead.

At Tuesdays meeting of the Renville County Board of Commissioners, fellow board members came wearing T-shirts proclaiming: In this county, nobody fights alone.

Organizers of the surprise sold 76 of the T-shirts to show support for Kramer and raise funds for the Renville County Walk in the Park campaign. More than 40 T-shirt wearing supporters joined the meeting via Zoom. Staff in the health department sang a song to express their support, and staff members told him they would keep him in their thoughts and prayers.

Thank you, said Kramer. He told the West Central Tribune that he was totally surprised by the display of support.

He has lots of support from family and friends, and its all-important. Kramer farms in eastern Renville County. He has lined up plenty of helping hands while he undergoes the stem cell transplant, which will sideline him for at least six weeks.

He said doctors are confident the stem cell transplant can knock the cancer into remission. They will be harvesting bone marrow cells and freezing a portion of them to make it possible to perform at least two more transplants in future years as well.

The decision to keep the date of that routine physical made all the difference. Absolutely, said Kramer.

Health providers told him that in too many cases, multiple myeloma is not diagnosed until a patient comes in with a broken leg or other bone, and wondering why. The cancer carves holes and weakens bones as it progresses unbeknownst to the person.

Thanks to the early diagnosis, Kramer said they found only pinholes in his bones, having caught the disease in the first of its three stages. He began chemotherapy in early January, and it has proven effective, he added.

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Keeping the physical appointment was critical, the show of support appreciated by Renville County Commissioner - West Central Tribune

Multiple myeloma is a type of cancer that originates from white blood cells called plasma cells. Many factors affect the outlook for a person with this disease, including their age, overall health, and kidney function, as well as the stage of cancer at diagnosis.

Multiple myeloma is a cancer of the plasma cells, which are a type of white blood cell. Over time, myeloma cells multiply and accumulate in the bone marrow and solid parts of the bones.

Multiple myeloma can lead to organ damage that affects the kidneys, the bones, and the overall immune system.

In this article, we look at the outlook for people with different stages of multiple myeloma. We also look at the symptoms and treatment of multiple myeloma and what can affect a persons outlook.

The American Cancer Society (ACS) estimates that doctors will diagnose 34,920 new cases of multiple myeloma in 2021 and that there may be 12,410 deaths from the disease.

When a person receives a multiple myeloma diagnosis, the doctor will use the Revised International Staging System (RISS) to determine the stage of the cancer. This staging system is based on:

A person will receive a diagnosis of either stage 1, 2, or 3 multiple myeloma. There is also a stage 0, a slow-growing type of multiple myeloma that is called smoldering myeloma.

However, survival rates are based on summary staging, which the Surveillance, Epidemiology and End Results (SEER) program developed. This staging system groups cancers into:

As multiple myeloma does not spread to the lymph nodes, the regionalized stage is not relevant to this cancer.

The 5-year relative survival rate for multiple myeloma is as follows:

These statistics mean that a person with localized multiple myeloma is 75% as likely as someone without multiple myeloma to live for 5 years after receiving the diagnosis.

People who receive a smoldering myeloma diagnosis can live for years without any treatment. Additionally, beginning treatment early does not appear to affect the outlook.

The stage of multiple myeloma is among the factors that can affect a persons outlook.

Other factors include:

A small 2014 study involving 82 people with an average age of 61 years found that those with damaged kidneys had a median survival rate of 13 months, whereas those without kidney damage lived for an average of 41 months.

Additionally, changes in chromosomes and genetic abnormalities can affect a persons outlook. The specific chromosomal abnormalities that doctors consider high risk affect chromosomes 4, 14, 16, and 17.

The treatment for smoldering myeloma typically consists of watchful waiting, as this stage is slow growing.

Drug therapy for multiple myeloma consists of:

Other treatment options include:

Multiple myeloma can cause:

A doctor may recommend supportive therapies to help manage these side effects. These may include surgery to help support weakened bones and prevent fractures.

Learn more about the treatment options and how to manage the symptoms.

A person should contact a healthcare professional if they notice any symptoms of multiple myeloma.

After receiving a multiple myeloma diagnosis, a person may want to ask the following questions:

Multiple myeloma is a type of cancer that affects the blood. The outlook for people with multiple myeloma depends on the stage of the cancer at the time of diagnosis. It also depends on how well a persons kidneys are functioning and their age and overall health.

However, different treatment options are available. A person should talk with a healthcare professional about which treatment options would best suit them.

Excerpt from:
Outlook for multiple myeloma: Figures and factors that affect it - Medical News Today

On the day of his Year 10 school prom, as other students excitedly prepared for the big occasion, then 15-year-old Rian Harvey was sat in a ward of Royal Marsden Hospital, awaiting the stem cell transplant that would save his life after a leukaemia relapse.

Despite the hot weather on that day back in July 2015, his hospital room windows had to remain sealed shut, as even the smallest bug bite could have killed him due to his compromised immune system.

Six years on, he finds himself grateful that he relapsed when he did, with five years to build his immunity before the Covid-19 pandemic hit.

Blood cancer patients are one of the most vulnerable groups of people at risk of Covid-19, according to research, being 57 per cent more likely to suffer severe disease compared to other cancer patients.

Recalling his own experience, Rian, now 22, says: Its scary, you look at everything that person has gone through, they had blood cancer and then had a stem cell transplant, they have gone through all the stress of only to be taken by a pandemic that came out of nowhere.

I know the vulnerability that you are in for stem cell transplants, Ive been there myself. Your immune system cant take anything.

Despite the high risk these patients face, charities such as Anthony Nolan, which assist blood cancer patients with finding a stem cell match, were left out of the allocated government budget that was announced in March.

The cancellation of face-to-face fundraising and events, despite the increase in demand for services, have led their gross income to be down by an estimated 5.5m for 2021.

Henny Braund, chief executive of the charity, said people with blood cancer and blood disorders were heavily impacted by the pandemic and everyone who needs treatment and support must be able to access it without delay.

This budget does not address the pressure currently facing cancer services across the UK, he adds.

Stem cell transplants are carried out to treat conditions such as blood cancer. The process involves removing the healthy stem cells of one person and transferring them to another, provided they have a similar or identical special genetic marker called the HLA.

While this match is sometimes present between family members, it is not always the case, leaving patients in the UK reliant on the British Bone Marrow Registry to find a suitable match. The odds of a match are one in 1000.

One of Anthony Nolans primary roles is to encourage more people to put themselves on the registry so patients have an increased chance to find a match. This can be done via a simple cheek swap, which provides sufficient HLA data for the initial matching process.

Will Briant, 24, from London, donated stem cells in 2015 after signing up to be on the registry at university. I think it ultimately is a huge part of who I am now, he says. Its something that I look to in my darker moments and find great inner strength from.

The identities of donors and recipients remain anonymous to one another, but they are allowed to exchange letters after the transplant.

I was incredibly emotional when I got the letter, he adds. He made it clear that not only was I giving him the chance of time for himself, but it was also for all of his family and friends, he told me he had a very big family. Looking back now, at a time where we cant all be with our families, it just highlights just how important and valuable that must have been for him.

Apart from encouraging people to sign up to the registry, the money Anthony Nolan raises go towards funding research, offering support and information to patients and families as well as providing post-transplant-care. They have helped 18,000 people find a match.

Unfortunately, they are part of the 35 per cent of charities who used the furlough scheme offered by the government to curb the loss of income. To ensure their survival, 24 per cent of surveyed charities said they were letting furloughed employees return as volunteers.

Terence Lovell, chief engagement and marketing officer at Anthony Nolan, says: We still desperately need funds to continue our life-saving work through providing stem cells transplants and co-ordinating efforts across the NHS to ensure patients receive the care and support they need.

Despite the circumstances, Rian has decided to make the most of his time in lockdown. He regularly shares his experience fighting cancer on his social media platforms and is currently in the process of writing a book and producing a podcast to further share his message.

The cancer mill is still very much open for business and I am trying to push people, that have not necessarily been through what Ive been through, to be more positive and see the world the way that I do, he says, I wake up in the morning, open my front door, take a deep breath of fresh air and I think this is amazing because five years ago I couldnt even open a window in the hospital.

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How Covid-19 has disrupted efforts to care for blood cancer patients - The Independent

Gene therapy has shown promise in recent years for treating a range of diseases, including sickle-cell anemia, hemophilia, various forms of inherited blindness, mesothelioma, and Duchenne muscular dystrophy. A new success story may soon be added to this list, with the publication yesterday of the outcomes of a clinical trial that used gene therapy to cure a rare immune system disorder in infants.

The study, described in the New England Journal of Medicine, was carried out by researchers from UCLA and Great Ormond Street Hospital in London over the course of five years, beginning in 2012.

Adenosine deaminase (ADA) is an enzyme found in a type of white blood cell called lymphocytes, which are primarily active in the brain, GI tract, and thymus gland. Lymphocytes make antibodies and attack infected cells, so theyre pretty crucial to the immune system.

ADAs job is to convert a molecule thats harmful to lymphocytes into a non-harmful version of itself. If ADA cant work its magic, that molecule starts to build up in lymphocytes, becoming toxic and ultimately killing the cellsand leaving the immune system virtually defenseless, highly vulnerable to invaders like viruses and bacteria.

Mutations in the ADA gene mean the body doesnt make enough of the enzyme to successfully do its job. This deficiency of ADA leads to a condition called severe combined immunodeficiency (SCID). Those suffering from SCID can not only get sick very easily, but conditions that would be neutralized by a normal immune system quickly become deadly for them.

SCID was more commonly known as bubble boy disease after David Vetter, a boy born in Texas in 1971, spent 12 of his 13 years of life enclosed in a plastic bubble to protect him from germs.

About 20 different genetic mutations can cause SCID; ADA-SCID refers to immunodeficiency caused by lack of the ADA enzyme: severe combined immunodeficiency due to adenosine deaminase deficiencya bit of a mouthful. The worst part of ADA-SCID is that it occurs in babies; most are diagnosed with the condition before theyre even six months old, and without treatment they typically dont live past age two.

ADA is rare, estimated to occur in about 1 in 200,000 to 1,000,000 newborns worldwide; both the mothers and the fathers ADA gene must have mutations for the child to end up with this condition.

The first step in the gene therapy treatment was to collect hematopoietic stem cells, which are those that manufacture blood cells, from the patients. The researchers then inserted an intact copy of the ADA gene into the stem cells using an RNA virus called a lentivirus (the most well-known lentivirus is HIV).

The altered cells were re-injected into the patients, where they started producing ADA normally, yielding healthy immune cells.

Out of 50 total patients30 in the US and 20 in the UKwith ADA-SCID, 48 appear to have been rid of their condition thanks to the gene therapy, with no complications reported. The two patients who didnt have success with the therapy went back to traditional treatment methods, and didnt experience any adverse effects as a result of having tried the therapy.

If, or hopefully when, gene therapy becomes the go-to treatment for ADA-SCID, it will be a welcome reprieve from traditional options, which are neither pleasant nor cheap: patients need weekly injections of ADA until a bone marrow transplant can be done, and absent a donor, they must consistently receive injections, take antibiotics, and undergo antibody infusions for life.

If approved in the future, this treatment could be standard for ADA-SCID, and potentially many other genetic conditions, removing the need to find a matched donor for a bone marrow transplant and the toxic side effects often associated with that treatment, said Dr. Claire Booth, co-author of the study and a consultant in pediatric immunology and gene therapy at Londons Great Ormond Street Hospital.

Theres no mention of the cost of the therapy, nor whether this could be a prohibitive factor to making it a viable option. Nonetheless, the study is encouraging not just for its potential to revolutionize treatment of ADA-SCID, but as a harbinger for the promise of gene therapy for a multitude of genetic conditions.

People ask us, is it a cure? Who knows long term, but at least up to three years, these children are doing well, said Dr. Stephen Gottschalk, who was not involved in this study but performed a similar gene therapy on kids with SCID at St. Jude Childrens Research Hospital in Memphis. The immune function seems stable over time so I think it looks very, very encouraging.

Image Credit: liyuanalison from Pixabay

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How One Round of Gene Therapy Fixed 48 Kids' Immune Systems - Singularity Hub

Dr Pria Suchak, 31, initially registered with blood cancer charity DKMS last July, when she was inspired by a message on social media.

Every 20 minutes someone in the UK is diagnosed with a blood cancer those that affect the body's bone marrow, blood or lymphatic system - such as leukaemia, myeloma or lymphoma.

Yet, only two per cent of the UK population are registered as potential blood stem cell donors.

Pria said: My friends nephew had leukaemia, so she was using her Facebook page to encourage strangers to sign up him.

"Her nephew is of mixed heritage - half Chinese and half Caucasian. So she was trying to encourage more people for minority ethnic communities to sign up.

"I wanted to help give someone a second chance of life, so I signed up with DKMS, and my husband registered at the same time.

Patients from black, Asian or other minority backgrounds have a 20 per cent chance of finding the best possible blood stem cell match from an unrelated donor, compared to 69 per cent for northern European backgrounds.

Pria ordered a home swab kit in July 2020 and was contacted by DKMS just five months later, informing her that she was a potential match for a stranger in need of a lifesaving blood stem cell transplant.

The mum-of-two said: I received a call from a lady at DKMS. She said I was extremely close to being a match, but there were also eight other people who were identified as possible matches too.

"A few weeks later, I received another call from DKMS saying that I was the best match out of the nine potential donors.

"I didnt expect that. As it was nine of us in total, you never expect you'll be chosen.

Following further tests and a medical examination, a date was set for Pria to donate her blood stem cells by peripheral blood stem cell collection (PBSC).

In the run-up to the procedure, donors are given a drug with the growth factor G-CSF to increase the number of stem cells in the blood.

Pria said: At the time I had so many things going on. We had just gotten past Christmas, both of my children had birthdays in January, and I was about to sit a final GP exam.

"DKMS were excellent and did their best to schedule my G-CSF injections the day after I sat the exam. Of course, they checked that this wouldnt impact the patient.

My actual donation was really nice, especially as there were other donors in the room at the same time donating for other patients.

"We all got on really well and chatted loads. The clinicians told us that we were the chattiest group they had ever had. Ive remained terrific friends with one of my fellow donors.

Because of the minimum two-year anonymity period in the UK, donors can only contact the patient anonymously, by letter or email.

Pria said: I dont know anything about my patient other than she is a woman. She really is a stranger, but I hope my blood stem cells help her to live a long life.

I strongly encourage people in Crawley to register with DKMS. By donating their blood stem cells, not only will you potentially help a stranger in desperate need, but you'll also help their family and friends by giving them more time together.

Crawley has a population of around 114,000 with 14 neighbourhoods, the largest inland town in West Sussex. Yet, just 865 residents have registered with DKMS.

On May 28, DKMS celebrates their day of awareness - World Blood Cancer Day. This May, the charity aims to register 2,000 new registrations (roughly one for every donor in the UK waiting) by the end of May 28.

If you are called upon to donate your blood stem cells it is because you are likely the patients best match.

There are two donation methods. Around 90 per cent of all donations are made through a method called peripheral blood stem cell (PBSC) collection.

This method is very similar to giving blood. It involves being connected to an apheresis machine. Apheresis means 'to separate'.

This machine separates blood being taken from one of the donor's arms, and separates the blood stem cells from it. The donor's blood is then returned to them through their other arm. This is an outpatient procedure that is usually completed in four-to-six hours.

In just ten per cent of cases, donations are made through bone marrow collection. Bone marrow is taken from the pelvic bone under general anaesthetic, and this lasts around an hour.

DKMS need blood stem cell donors from all backgrounds. If you are aged between 17-55 and in good general health, you can support Gareth and the other 2,000 people in need of a lifesaving blood stem cell transplant by registering online at http://www.dkms.org.uk/register-now for your home swab kit.

By registering, you'll join a group of over 840,000 other DKMS lifesavers-in-waiting, ready to make a difference by giving someone a much-needed second chance of life.

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Crawley GP urges residents to save the life of a stranger - Crawley Observer

CLEVELAND When 61-year-old Ken Anderson was diagnosed with Multiple Myeloma 3 years ago, he didnt know what to expect.

It kind of hits you. It hits you hard, he said. Its a blood cancer, and its in your bone marrow, and it degenerates your bones is what it does.

The cancer is incurable, but treatable.

You live with it and you have to have many rounds of chemotherapy to keep the myeloma at bay, said Dr. Ted Teknos, the president of University Hospitals Seidman Cancer Center.

With so many unknowns, the dad of 4 girls and grandfather of 2 knew one thing, he was going to fight.

You just have to look to the road ahead, he said.

For the past 3 years, that road has been filled with ups and downs and countless rounds of chemotherapy treatments and even a bone marrow transplant.

They give you your stem cells back and those regenerate and lasted for about 6 months, and then there was a relapse, said Anderson.

Through it all, he remained hopeful for a medical breakthrough. He read about the research and followed up on the results of clinical trials in something called CAR T therapy.

I didn't know how far out that would be. It didn't say how far out it was. It sounded, to me, something like 10 or 20 years.

But it wasnt 20 years, the FDA approved CAR T therapy for Multiple Myeloma patients, and University Hospitals is the first in Ohio to treat patients with it. Anderson, who is from Kirtland, is the first patient in Ohio to receive it.

These treatments, now, are available for those that have run out of options, said Dr. Teknos.

Dr. Teknos compared the treatment to something straight out of a science fiction movie.

In essence, its like a heat-seeking missile for the cells to go find the cancer and eradicate it, he said.

It works by taking a patients own white blood cells, genetically modifying them in a lab and then infusing them back into their body so the patients cells can fight off the cancer cells.

They will engineer them to attack my cancer cells, said Anderson.

Dr. Teknos calls it living therapy.

You're taking living cells out of a patient, you're modifying them, and then you're growing them up in the lab and then re-infusing them back into the patient, he said. It's their own cells that have been modified and fight the cancer.

Dr. Teknos said in clinical trials, about 75% of Multiple Myeloma patients had a response to therapy, and in 1/3 of patients, their cancer went away.

Its really a game changer, said Dr. Teknos. There are patients who literally had weeks to live and then a year and a half later, have no cancer at all.

Andersons cells are currently in the lab. He will receive his infusion next month. He is cautiously optimistic that the next stop on his journey will have him feeling better.

I won't have to be on the chemo anymore, so I'm just back to feeling like myself would be would be really exciting, he said. People who are out there and diagnosed with this, with this disease, know that we are on the cusp of some big things here in the treatment of it, and this is a huge advance.

While Anderson is currently fighting Multiple Myeloma, University Hospitals is also offering a new CAR T cell therapy treatment for patients diagnosed with Diffuse Large B-Cell Lymphoma.

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University Hospitals treats first cancer patient in Ohio with "game changing" CAR T therapy - News 5 Cleveland