Cancer is an extremely complex disease. There are over 200 different types, some of which are considered common and others which are classified as rare cancers. But what exactly does it mean if a cancer is rare?

Usually, it means it only affects a small handful of people, but doctors might also call a cancer rare if it starts in an uncommon place in the body, or if the cancer is an unusual type and requires special treatment.

For secondary central nervous system (CNS) lymphoma, its an incredibly rare cancer for a combination of these reasons.

Secondary CNS lymphoma is a type of lymphoma thats spread to the brain and spinal cord nervous system after originating elsewhere in the body. And as well as being a rare cancer, secondary CNS lymphoma is an aggressive cancer, which has relatively low survival rates.

However, the latest results from the Stand Up To Cancer-funded MARIETTA clinical trial, which details a new potentially transforming treatment, has shed a glimmer of hope for patients and doctors alike.

We spoke to Dr Kate Cwynarski, who led the study in the UK, about what the latest results could mean for patients with secondary CNS lymphoma.

With a rare cancer such as secondary CNS lymphoma, finding a large enough group of patients can be a real challenge. And in cases like this, researchers have to think on a global scale.

Its a rare disease. So the reality of it is that you would not get this information if we just performed a trial in the UK, says Cwynarski. International collaboration is the only way to do it.

The MARIETTA trial is the largest study focused on patients with secondary CNS lymphoma, involving 24 centres across 4 countries and recruiting a total of 79 patients. It involved the International Extranodal Lymphoma Group (IELSG) lead by Professor Andres Ferreri in Italy and it built on the success of prior research with this group. In the UK, the trial was managed by CRUK Southampton CTU.

In particular, findings from a previous clinical trial partly funded by us, which tested treatments for primary CNS lymphoma, a lymphoma thats only found in the brain, helped inform the design of this clinical trial.

The IELSG-32 trial tested the benefits of an intensive chemotherapy regimen known as MATRIX, followed by either whole brain radiotherapy or a stem cell transplant using the patients own cells.

Cwynarski describes the IELSG-32 trial as practice changing, and its from these impressive results that the MARIETTA trial was developed. So we adapted a strategy that was successful in treating primary CNS lymphoma in the IELSG-32 trial and added another chemotherapy regimen, called R-ICE, to help treat the systemic disease on top of the secondary brain disease.

Cwynarski specialises in lymphoma, so she has treated SCNSL patients both on and off the trial. One of the big benefits of this trial, she describes, is that the inclusion criteria for the cohort more accurately reflected the patients she sees in her clinic and referral practice.

This trial included patients up to 70 years of age. And it wasnt just focused on fit, young people. So I have to say I think it was meaningful, because it included the kind of patients that we actually see.

The trial also included people regardless of when their secondary CNS lymphoma was diagnosed, whether that was when someone was originally diagnosed with lymphoma, during treatment, or after their cancer had come back.

And the results look promising. A total of 49 patients (65%) responded to the treatment in some way, with 37 people going on to have a stem cell transplant. 100% of the patients who had the stem cell transplant had not seen their cancer recur a year after registering onto the trial. We are optimistic many will be cured of this aggressive lymphoma.

But the trial also picked up differences between groups. While the regime was effective to an extent in every sub-group, the most significant results were seen in patients whose CNS disease was discovered at initial lymphoma diagnosis. Within this group, 71% of patients had lived for 2 years without their cancer growing.

A result which has never been seen before.

The results of the trial have completely transformed the teams optimism when meeting new patients. We really have identified a regimen which is intensive, but its potentially curative, concludes Cwynarski, and the word cure is not something weve really used before when talking about this disease.

Recently, Cwynarski has been busy filling out a cohort of her patients DVLA forms, confirming they are fit to drive again after being 2 years treatment free. So thats an amazing success and it was very symbolic as a reminder that these people have been alive and off all treatment for 2 years.

Moments like this are a reflection of the huge impact the MARIETTA trial has had for real people, like Maureen Brewster.

Maureen was diagnosed with lymphatic cancer of the liver in 2011 and was under the watchful eyes of a consultant during her treatment. But in the summer of 2016, I started to have very extreme headaches, says Maureen.

After getting an emergency appointment, she was taken to A&E and admitted to hospital straight away. I was transferred to the National Neurology hospital in Russell Square for a biopsy. They thought I might have had a stroke. But it wasnt. Instead, Maureen was diagnosed with a secondary cancer in her brain.

When Maureen was transferred to UCLH, she was told about the MARIETTA trial. I could have chosen not to go on the trial, but being part of it meant that I would get more examinations and monitoring. So it was more reassuring to be on the trial, she says.

Maureen during treatment.

Maureen went through 8 tough months of chemotherapy before having a stem cell transplant in the summer of 2017. During one round of chemo in the hospital I became ill with an infection and really thought I was going to die. The last chemo prior to me having stem cell transplant was so strong it really had an impact on me and I couldnt eat I felt very poorly for a few weeks.

Maureens stem cell transplant went smoothly and prior to COVID-19, she was having regular check-ups and scans in hospital.

Prior to the first lockdown in March 2020, Maureen was able to do some volunteering and also go back to work, teaching a course on Project Management at a local adult college. In April 2019 I also secured a part-time job as a User Involvement Co-ordinator. It was great to get back to that level.

Dr Cwynarski emphasises that while the trial was a great success for some, it also exposed a group of patients who didnt do so well on the treatment.

The results threw up a real disparity and uncovered an unmet need in a particular group of patients. For the group of patients whose cancer had already failed to respond to a chemotherapy treatment, known as R-CHOP, at the follow up of 2 years, only 20% had not experienced their cancer progressing or getting worse.

We need to target this cohort of patients in a different way, says Cwynarski. So really the challenge is, can we identify experimental agents be it different biological agents or immunotherapies such as CAR T cell therapy in the patients who have relapsed, and maybe bringing these therapies into the frontline.

Lilly

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Transforming optimism: finding new ways to treat rare cancers - Cancer Research UK - Science Blog

Spinal Cord Stem Cells Comments Off on Transforming optimism: finding new ways to treat rare cancers – Cancer Research UK – Science Blog | January 29th, 2021

Stem Cell Therapy Market is valued at USD 9.32 Billion in 2018 and expected to reach USD 16.51 Billion by 2025 with the CAGR of 8.5% over the forecast period.

Rising prevalence of chronic diseases, increasing spend on research & development and increasing collaboration between industry and academia driving the growth of stem cell therapy market.

Scope of Stem Cell Therapy Market-

Stem cells therapy also known as regenerative medicine therapy, stem-cell therapy is the use of stem cells to prevent or treat the condition or disease. Stem cell are the special type of cells those differentiated from other type of cell into two defining characteristics including the ability to differentiate into a specialized adult cell type and perpetual self-renewal. Under the appropriate conditions in the body or a laboratory stem cells are capable to build every tissue called daughter cells in the human body; hence these cells have great potential for future therapeutic uses in tissue regeneration and repair. Among stem cell pluripotent are the type of cell that can become any cell in the adult body, and multipotent type of cell are restricted to becoming a more limited population of cells.

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The stem cell therapy has been used to treat people with conditions including leukemia and lymphoma, however this is the only form of stem-cell therapy which is widely practiced. Prochymal are another stem-cell therapy was conditionally approved in Canada in 2012 for the treatment of acute graft-vs-host disease in children those are not responding to steroids. Nevertheless, hematopoietic stem cell transplantation is the only established therapy using stem cells. This therapy involves the bone marrow transplantation.

Stem cell therapy market report is segmented based on type, therapeutic application, cell source and by regional & country level. Based upon type, stem cell therapy market is classified into allogeneic stem cell therapy market and autologous market.

Stem Cell Therapy Companies:

Stem cell therapy market report covers prominent players like,

Based upon therapeutic application, stem cell therapy market is classified into musculoskeletal disorders, wounds and injuries, cardiovascular diseases, surgeries, gastrointestinal diseases and other applications. Based upon cell source, stem cell therapy market is classified into adipose tissue-derived mesenchymal stem cells, bone marrow-derived mesenchymal stem cells, cord blood/embryonic stem cells and other cell sources

The regions covered in this stem cell therapy market report are North America, Europe, Asia-Pacific and Rest of the World. On the basis of country level, market of stem cell therapy is sub divided into U.S., Mexico, Canada, U.K., France, Germany, Italy, China, Japan, India, South East Asia, GCC, Africa, etc.

Stem Cell Therapy Market Segmentation

By Type

Allogeneic Stem Cell Therapy Market, By Application

Autologous Market, By Application

By Therapeutic Application

By Cell Source

Stem Cell Therapy Market Dynamics

Rising spend on research and development activities in the research institutes and biotech industries driving the growth of the stem cell therapy market during the forecast period. For instance, in January 2010, U. S. based Augusta University initiated Phase I clinical trial to evaluate the safety and effectiveness of a single, autologous cord blood stem infusion for treatment of cerebral palsy in children. The study is estimated to complete in July 2020. Additionally, increasing prevalence of chronic diseases creating the demand of stem cell therapy. For instance, as per the international diabetes federation, in 2019, around 463 million population across the world were living with diabetes; by 2045 it is expected to rise around 700 million. Among all 79% of population with diabetes were living in low- and middle-income countries. These all factors are fuelling the growth of market over the forecast period. On the other flip, probabilities of getting success is less in the therapeutics by stem cell may restrain the growth of market. Nevertheless, Advancement of technologies and government initiative to encourage research in stem cell therapy expected to create lucrative opportunity in stem cell therapy market over the forecast period.

Stem Cell Therapy Market Regional Analysis

North America is dominating the stem cell therapy market due increasing adoption rate of novel stem cell therapies fueling the growth of market in the region. Additionally, favorable government initiatives have encouraging the regional market growth. For instance, government of Canada has initiated Strategic Innovation Fund Program, in which gov will invests in research activities carried out for stem cell therapies. In addition, good reimbursing scheme in the region helping patient to spend more on health. Above mentioned factors are expected to drive the North America over the forecast period.

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Stem Cell Therapy Market 2021: Global Key Players, Trends, Share, Industry Size, Segmentation, Forecast To 2027 KSU | The Sentinel Newspaper - KSU |...

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EIMEAR Gooderham (ne Smyth) was just 25 when she died peacefully in hospital with her family at her bedside.

It was just a week after she had married Phillip Gooderham in hospital and she was buried in the wedding dress she never got to wear.

Almost two years on, her family hope a television documentary about Eimear - a make-up artist from the Coolnasilla area of west Belfast - will help create a positive and lasting legacy in her memory.

The programme, due to be broadcast on UTV and presented by journalist Sarah Clarke, features Eimear's own video diaries, which she had hoped would raise awareness of a campaign for stem cell donors that she launched before her death.

Ms Clarke said the documentary had aimed to "follow Eimear's journey, treatment and her recovery".

"She was very open about her battle and while a lot of the programme is distressing, it shows how courageous Eimear was," she said.

Eimear was diagnosed with stage two Hodgkins Lymphoma, a type of blood cancer, in September 2016.

She underwent 12 cycles of intensive chemotherapy and was given the all-clear in spring 2017.

But the disease returned and in December that year, Eimear was treated with an autologous stem cell transplant, intensive chemotherapy and her own stem cells returned afterwards to rescue her bone marrow from the effect of the treatment.

Months later she was given the good news she was in remission, but the Hodgkins Lymphoma returned again and doctors said her best chance of survival was another stem cell transplant - this time from a donor.

With neither of her siblings a match, she desperately needed to find a stem cell donor.

Eimear and her father Sean launched an appeal to raise awareness of the stem cell register, which allows donors of the correct tissue types to be matched with patients.

Their campaign saw the number of people joining the register in Northern Ireland soar.

Determined to use her own experience to help others, Eimear began filming videos on her phone for the UTV documentary.

Her desire to show her cancer battle as well as her upbeat outlook on life are reflected in the diaries, with many filmed as she underwent treatment.

Speaking ahead of the broadcast tonight, Ms Clarke said her own family's cancer battle had also inspired her to tell Eimear's story.

"In 2017, my nephew Jack was diagnosed with leukaemia, aged just 15," she said.

"I remember my brother Simon, who is a doctor, saying they may have to pursue a stem cell transplant. He knew how difficult it would be to find a match and to endure.

"Fortunately Jack didn't need it, but he had to undergo a year of intensive chemo and four years of maintenance chemo.

"It was rough and a very difficult period and thankfully he's now in remission, but it made me relate to Eimear and San's appeal."

On October 31 2018 - a year before Eimear and Phillip had planned to marry - she received her stem cell transplant.

A video extract of the days after the operation shows Eimear describe how "it's been really rough", as the donor's cells began attacking her cells - a condition known as graft versus host disease.

Despite being discharged from hospital, months later she became ill again with complications associated with the transplant - she was losing her brave battle.

Phillip tells the programme: "I wanted to tell her it was going to be ok, but I didn't want to lie to her. I wanted it to be over so she wasn't in pain".

In June 2019, the couple tied the knot and Eimear got "her final wish".

"We had had it planned, we had to cancel our wedding so it was, in the most horrific circumstances, the nicest way to end her life, by her getting her final wish," said Phillip.

Eimear died on June 27 2019.

Since then her family have continued to campaign to raise awareness of stem cell donation.

Her father Sean said they hope the programme will "highlight the need for more people in Northern Ireland to join the stem cell donor register, especially young men aged between 16 and 30".

Sarah also said while the documentary is "not exactly the one we set out to make, its still one of hope and courage".

"It was Eimears dying wish to raise awareness of stem cell donation and to help further research into the treatment to help others," she said.

"She was adamant she wanted people to sign the register and raise awareness. Her family feel the onus is now on them to continue this.

"The programme pays tribute to a courageous young woman and her family's desire to create a positive and lasting legacy in her memory."

Up Close: Eimears Wish is on UTV at 10.45pm.

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UTV documentary tells of young Belfast woman's lasting legacy to promote stem cell donation - The Irish News

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National Institute for Health and Care Excellence (NICE) recommends lenalidomide as a maintenance therapy for people with newly diagnosed multiple myeloma who have undergone a stem cell transplant

Uxbridge, UK, 27th January 2021: Celgene, a Bristol Myers Squibb (BMS) company, today announces that NICE has issued a Final Appraisal Document (FAD) recommending REVLIMID (lenalidomide) as maintenance treatment after an ASCT for newly diagnosed multiple myeloma in adults.[iv] From today, approximately 1150 eligible patients in England will have immediate access to lenalidomide as a treatment option, with interim funding provided via the Cancer Drugs Fund (CDF) before transferring to baseline commissioning. Lenalidomide is the first treatment to be made available on the NHS in this setting and provides an alternative to the standard watch-and-wait approach, allowing patients to receive active treatment to keep their cancer in remission.

Graham Jackson, Professor of Clinical Haematology at Newcastle Upon Tyne NHS Foundation Trust said: Multiple myeloma is a relapsing remitting disease where the goal of treatment is to ensure long periods of remission and a good quality of life. Maintenance therapy is integral to achieving this, particularly for newly diagnosed patients who have received a stem cell transplant. Having lenalidomide within our treatment armoury on the NHS will transform the way we manage the early stages of multiple myeloma. In clinical studies maintenance therapy has been shown to almost double the initial period of remission for this group of patients, so it is fantastic to be able to offer active treatment which can help to keep the cancer at bay.

Multiple myeloma is a cancer that affects the production of plasma cells in the bone marrow and in turn impacts the bodys immune system.[v] It is characterised by a relapsing-remitting pattern, which means that the disease goes through periods where the cancer is active and needs treatment, followed by periods where it is under control.[vi] Each time the cancer relapses, the length of time spent in remission shortens.[vii] The objective of maintenance therapy is to control the cancer during the period of remission and delay relapse of the disease.[viii]

Laura Kerby, Chief Executive of Myeloma UK said: We are delighted with this outcome. Patients who receive lenalidomide maintenance after high-dose therapy and stem cell transplant have a significant increase in overall survival, so the decision to make this available through the NHS is fantastic news.

Across the UK, around 1,500 newly diagnosed multiple myeloma patients undergo an ASCT each year,1,2 and most of them will eventually relapse.[ix] This first remission is a critical period for people with multiple myeloma, as it can be an indicator of the overall survival of the disease and it has been shown that effective maintenance therapy could be essential to long-term survival.[x]

Lynelle Hoch, General Manager at Bristol Myers Squibb UK & Ireland commented: Todays announcement marks an important milestone for those living with multiple myeloma, with lenalidomide being the first maintenance treatment option to be made accessible to eligible patients in England. We are grateful for the continued collaboration with NICE, healthcare professionals and Myeloma UK to ensure patients can benefit from lenalidomide in this setting.

Following the publication of this guidance, the NHS in Wales is expected to provide funding and resources for lenalidomide in this setting within two months. The treatment is already available on the NHS in Scotland and in Northern Ireland.[xi],[xii]

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National Institute for Health and Care Excellence (NICE) recommends lenalidomide as a maintenance therapy for people with newly diagnosed multiple mye...

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NEW YORK, Jan. 28, 2021 /PRNewswire/ --BrainStorm-Cell Therapeutics Inc. (NASDAQ: BCLI), a leader in developing innovative autologous cellular therapies for highly debilitating neurodegenerative diseases, announced today that the Company will hold a conference call to update shareholders on financial results for the fourth quarter and year ended December 31, 2020, and provide a corporate update, at 8:00 a.m., Eastern Time, on Thursday, February 4, 2020.

BrainStorm's CEO, Chaim Lebovits, will present a corporate update, after which, participant questions will be answered. Joining Mr. Lebovits to answer investment community questions will be Ralph Kern, MD, MHSc, President and Chief Medical Officer, Stacy Lindborg, PhD, Executive Vice President and Global Head of Clinical Research ,David Setboun, PharmD, MBA, Executive Vice President and Chief Operating Officer, Preetam Shah, PhD, MBA, Executive Vice President and Chief Financial Officer.

Participants are encouraged to submit their questions prior to the call by sending them to: q@brainstorm-cell.com. Questions should be submitted by 5:00 p.m. EDT, Wednesday, February 3, 2020.

The investment community may participate in the conference call by dialing the following numbers:

Participant Numbers:

Toll Free: 877-407-9205

International: 201-689-8054

Webcast URL: https://cutt.ly/vjBvkTp

Those interested in listening to the conference call live via the internet may do so by visiting the "Investors & Media" page of BrainStorm's website at http://www.ir.brainstorm-cell.com and clicking on the conference call link.

Those that wish to listen to the replay of the conference call can do so by dialing the numbers below. The replay will be available for 14 days.

Replay Number:

Toll Free: 877-481-4010

International: 919-882-2331

Replay Passcode: 39495

About NurOwn

The NurOwn technology 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 can 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.

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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 NurOwn technology platform used to produce autologous MSC-NTF cells through an exclusive, worldwide licensing agreement. Autologous MSC-NTF cells have received Orphan Drug status designation 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 is in active discussions with the FDA to identify regulatory pathways that may support NurOwn's approval in ALS. BrainStorm is also conducting an FDA-approved phase 2 open-label multicenter trial in progressive multiple sclerosis (MS). The phase 2 study of autologous MSC-NTF cells in patients with progressive MS (NCT03799718) completed dosing in December 2020, and topline results are expected by the end of the first quarter 2021.

For more information, visit the company's website at http://www.brainstorm-cell.com.

ContactsInvestor Relations:Corey Davis, Ph.D.LifeSci Advisors, LLCPhone: +1 646-465-1138cdavis@lifesciadvisors.com

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

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SOURCE Brainstorm Cell Therapeutics Inc

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BrainStorm-Cell Therapeutics to Announce Fourth Quarter and Fiscal Year 2020 Financial Results and Provide a Corporate Update - Yahoo Finance

Bone Marrow Stem Cells Comments Off on BrainStorm-Cell Therapeutics to Announce Fourth Quarter and Fiscal Year 2020 Financial Results and Provide a Corporate Update – Yahoo Finance | January 29th, 2021

[Courtesy of ToolGen]

SEOUL --ToolGen, a South Korean developer of genome editing technology, tied up with T&R Biofab, a 3D bioprinting company, to cooperate in applying induced pluripotent stem cells to gene correction. ToolGen has original technology related to third-generation gene scissors to cut out genetic information in cells.

Induced pluripotent stem cells (iPSCs) are derived from skin or blood cells that have been reprogrammed back into an embryonic-like pluripotent state that enables the development of an unlimited source of any type of human cell needed for therapeutic purposes. iPSCs can be derived directly from adult tissues and bypass the need for embryos.

ToolGen signed a memorandum of understanding T&R Biofab, which prints human organs and tissues for clinical transplantation, to develop and utilize cells that combine iPSCs and gene calibration technologies. "Inductive pluripotent stem cells are an ideal platform for developing gene correction therapy because they can be segmented into various cells," said ToolGen co-CEO Kim Young-ho.

ToolGen has partnered with VivaZome Therapeutics, an Australian biotech company, to develop therapies based on exosomes which are recognized for their critical role in cell-to-cell communication and transportation. The market for exosome therapeutics has been growing rapidly, and many life science companies have launched tools and systems to support exosome research.

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ToolGen ties up with 3D bioprinting company to apply induced pluripotent stem cells to gene correction - Aju Business Daily

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News Release

Thursday, January 28, 2021

Approach could provide new path for difficult-to-treat forms of Leber congenital amaurosis.

Scientists at the National Eye Institute (NEI) have developed a promising gene therapy strategy for a rare disease that causes severe vision loss in childhood. A form of Leber congenital amaurosis, the disease is caused by autosomal-dominant mutations in the CRX gene, which are challenging to treat with gene therapy. The scientists tested their approach using lab-made retinal tissues built from patient cells, called retinal organoids. This approach, which involved adding copies of the normal gene under its native control mechanism, partially restored CRX function. The study report appears today in Stem Cell Reports. NEI is part of the National Institutes of Health.

Our treatment approach, which adds more copies of the normal gene, could potentially treat autosomal-dominant LCA caused by a variety of mutations, said Anand Swaroop, Ph.D., chief of the NEI Neurobiology, Neurodegeneration and Repair Laboratory and senior author of the report.

The U.S. Food and Drug Administration approved Luxturna in 2017 for the treatment of LCA patients with mutations in a gene called RPE65. Although hailed as a major advance in gene therapy, Luxturna is ineffective against other forms of LCA, including those caused by autosomal-dominant mutations in CRX.

The CRX gene encodes a protein (also called CRX) that binds to DNA and instructs the retinas photoreceptors to make light-sensitive pigments called opsins. Without functional CRX protein, photoreceptors lose their ability to detect light and eventually die.

Disorders like autosomal-dominant LCA are tricky to treat with gene therapy, because adding more of the normal gene does not always restore function. People with autosomal-dominant mutations still have one normal copy of the gene, but the mutant version of the protein interferes with the normal protein. Sometimes, instead of restoring normal function, simply adding more of the normal protein can enhance the disease in unpredictable ways.

To explore how gene augmentation adding copies of the normal gene would affect autosomal-dominant LCA, Swaroops team, developed retinal organoids from two volunteers with LCA and from their unaffected family members. Led by Kamil Kruczek, Ph.D., a postdoctoral fellow in Swaroops lab, they built the complex retina-like tissues in several stages, starting with skin cells, inducing the production of mature photoreceptors and other retinal cells with the genetic profile of each volunteer. As expected, patient organoids made far less light-sensing opsin than the organoids made from unaffected family members.

To carefully control how much CRX gene would be expressed by the recipient photoreceptors, the team re-engineered the CRX promoter so it could be delivered with the CRX gene as part of the gene therapy. A promoter is a neighboring sequence of DNA that controls when and how genes are expressed. The researchers packed the gene and their engineered promoter inside a virus that shuttled them into the organoid photoreceptors.

The teams gene augmentation strategy restored some CRX protein function for organoids from both patients, driving expression of opsins in both types of photoreceptors: rods and cones.

The fact that this strategy worked for both CRX mutations was pretty exciting, said Swaroop. Gene augmentation may be a viable therapy for LCA caused by other autosomal-dominant mutations.

This proof-of-concept gene therapy study is the first step toward a potential treatment for a rare form of LCA, said Brian Brooks, M.D., NEI clinical director and co-author on the study. Its a great example of bench-to-bedside science, when researchers in basic and clinical science collaborate.

The current study was funded through the intramural programs of the NEI and the National Institute of Allergy and Infectious Diseases, both part of NIH. Patient samples were collected at the NIH Clinical Center, clinical trial number NCT01432847.

NEI has protected intellectual property around this technology which is available for licensing and or co-development. Details can be found on the NIH OTT Licensing website: Gene Therapy for Treatment of CRX-Autosomal Dominant Retinopathies | Office of Technology Transfer, NIH or by contacting NEI Office of Translational Research mala.dutta@nih.gov

Additional authors include: Zepeng Qu, James Gentry, Benjamin Fadl, Linn Gieser, Suja Hiriyanna, Zacahry Batz, Mugdha Samant, Ananya Samanta, Colin Chu, Laura Campello, and Zhijian Wu.

NEI leads the federal governments research on the visual system and eye diseases. NEI supports basic and clinical science programs to develop sight-saving treatments and address special needs of people with vision loss. For more information, visit https://www.nei.nih.gov.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIHTurning Discovery Into Health

Kruczek K. Qu Z, Gentry J, Fadl BR, Gieser L, Hiriyanna S, Batz Z, Samant M, Samanta A, Chu CJ, Campello L, Brooks BP, Wu Z, and Swaroop A. Gene therapy of dominantCRX-Leber congenital amaurosis using patient stem cell-derived retinal organoids.Stem Cell Reports, January 28, 2020.https://doi.org/10.1016/j.stemcr.2020.12.018

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If you have cancer and your doctor recommends Opdivo to treat it, you may be wondering what side effects this drug might cause.

Opdivo (nivolumab) is a brand-name prescription medication used in adults to treat certain types of cancer. These include specific forms of bladder, colorectal, and esophageal cancer, as well as several other cancer types. Its also used in some children to treat colorectal cancer.

Opdivo is a biologic drug (a type of drug made from living cells). Specifically, its an immunotherapy treatment, which means it can cause side effects involving your immune system. Its given as an intravenous infusion (an injection into a vein thats given over a period of time). For more information about Opdivo, see this in-depth article.

Opdivo may be a long-term cancer treatment. Your doctor will decide the length of your treatment based on various factors, including what side effects you experience.

Read on to learn more about the possible mild and serious side effects of Opdivo.

Like all drugs, Opdivo may cause side effects in some people.

The more common side effects of Opdivo include:

For more information about rash as well as muscle, bone, and joint pain, see the Side effects explained section below.

Certain side effects may be more common if other cancer drugs, such as ipilimumab (Yervoy), are part of your treatment plan. You may have a higher risk for certain side effects depending on the type of cancer you have.

Talk with your doctor about your risk for side effects, given your specific treatment plan. Also tell them about any side effect symptoms you may have.

Learn more about Opdivos side effects in the next sections.

You may experience mild side effects with Opdivo, such as:

For more information about muscle, bone, and joint pain, see the Side effects explained section below.

Opdivo may cause mild side effects other than the ones listed above. See the Opdivo Medication Guide for details.

Opdivos mild side effects should be manageable, and theyll likely go away during your treatment. But some could also be signs of more serious side effects.

If any side effects bother you, get worse, or dont go away, talk with your doctor or pharmacist. Try to keep all of your appointments to get Opdivo unless your doctor stops your treatment.

Opdivo may cause serious side effects. While these are generally rare, some people may be at higher risk for certain serious side effects. For example, your risk for some side effects may increase if youre receiving both Opdivo and other drugs for your cancer.

Call your doctor right away if youre having any new or worsening symptoms. If your symptoms feel life threatening, call 911 or get emergency medical care right away.

Serious side effects can include:

For more information on hepatitis, type 1 diabetes, and allergic reaction, see the Side effects explained section below.

Talk with your doctor about your risk for serious side effects. Also let them know about any concerns you may have.

Get answers to some frequently asked questions about Opdivos side effects.

No, Opdivo shouldnt cause confusion. In clinical studies of Opdivo, confusion wasnt a reported side effect.

However, confusion may be a symptom of rare, serious side effects of Opdivo, such as:

Also, Opdivo can cause hyponatremia (low blood sodium levels). Confusion is a symptom of this condition, which was a common side effect in certain clinical studies of Opdivo.

If youre feeling disoriented or having trouble thinking clearly during Opdivo treatment, contact your doctor right away.

In clinical studies of Opdivo as a melanoma treatment, reported side effects were similar to those researchers found when looking at the drug to treat other cancers.

However, Opdivo isnt always used alone to treat melanoma. The risk of side effects may differ depending on your treatment plan. For more information, see the Opdivo Medication Guide.

If youre receiving Opdivo infusions to treat melanoma, ask your doctor about your side effect risks.

Side effects with Opdivo can happen at any time, including after stopping treatment.

For example, severe reactions have happened during Opdivo infusions. However, these are rare compared with mild or moderate infusion-related reactions. Some people have had reactions within 2 days after their infusion, although these are rare as well.

Opdivo may cause your immune system to attack healthy tissues or organs. This can happen anytime during or after stopping Opdivo treatment.

Symptoms of a severe reaction that may happen during an Opdivo infusion can include:

If you have these or other symptoms during an Opdivo infusion, immediately tell the healthcare provider who is giving you the infusion.

Though rare, people have had reactions up to 2 days after their infusion. You should watch for any new or bothersome symptoms on the days between your infusions, too.

If you have a severe reaction, your healthcare provider may stop your Opdivo infusion. If you have a mild or moderate reaction during your infusion, they may slow the rate of infusion or pause it to help manage your symptoms.

Yes, it can. For example, Opdivo treatment could increase your risk for pneumonia. Pneumonia is a serious infection of the air sacs in one or both of your lungs.

In clinical studies for certain cancers, pneumonia was one of the more common serious reactions when Opdivo was used alone or with the cancer drug ipilimumab (Yervoy).

In clinical studies for certain cancers, rare but fatal infections have also occurred when Opdivo was used alone or with other cancer drugs.

Upper respiratory tract infection, such as a cold, is a common side effect of Opdivo. Though upper respiratory tract infections arent usually serious, they can lead to secondary infections such as pneumonia.

See your doctor if you have any infection symptoms such as a cough, shortness of breath, or fever.

Learn more about some of the side effects Opdivo may cause.

You may have painful joints from treatment with Opdivo. Joint pain is a common side effect of the drug.

Muscle, back, and bone pain are also common side effects of Opdivo.

Opdivo can cause your immune system to attack healthy tissues, even after youve stopped the drug. This can happen to any part of your body, including your joints. Rarely, arthritis (swelling in your joints) has occurred with Opdivo treatment.

If youre experiencing pain in your joints or other areas of your body during or after Opdivo treatment, talk with your doctor. They can check your symptoms and suggest ways you can manage them.

For mild joint pain, they may recommend you take an over-the-counter pain reliever, such as ibuprofen (Advil or Motrin). They may also suggest applying ice packs or warm compresses to your joints.

Rash is a common side effect of Opdivo.

In rare cases, Opdivo may cause a severe skin reaction, such as Stevens-Johnson syndrome. It may also result in allergic reactions, which may be mild or serious. Rash can be a symptom of both of these reactions.

During and after Opdivo treatment, contact your doctor if you have a rash that bothers you, gets worse, or doesnt go away. Get emergency medical care right away if you have blisters, peeling skin, or rash accompanied by fever, swelling, or trouble breathing. These could be signs of a severe, life threatening reaction.

If your symptoms are mild to moderate, your doctor may suggest that you manage them with a topical cream or ointment, such as hydrocortisone cream.

If youre having a severe skin reaction, your healthcare provider will pause or permanently stop your Opdivo infusions. Theyll manage the reaction with corticosteroids, such as prednisone, or other immune-suppressing drugs.

Though rare, Opdivo treatment may cause your immune system to attack healthy tissues, including your liver. When this happens, it can cause inflammation (swelling and damage) of your liver known as hepatitis.

This side effect may be more likely to happen if your treatment plan includes both Opdivo and the cancer drug ipilimumab (Yervoy).

If you have hepatitis from Opdivo treatment, your healthcare provider will pause or permanently stop your infusions. Theyll manage the condition with a corticosteroid drug, such as prednisone. In some cases, you may need to take another immune-suppressing drug.

During and after stopping Opdivo treatment, tell your doctor if you have any symptoms of hepatitis, such as:

Rarely, Opdivo may cause type 1 diabetes. With type 1 diabetes, your blood glucose (sugar) level becomes too high because your pancreas isnt releasing insulin. If untreated, this can lead to serious complications. An example is diabetic ketoacidosis (high levels of blood acids called ketones), which can be fatal.

Your doctor may check your blood glucose level while youre getting Opdivo. During and after your treatment, watch for any diabetes or ketoacidosis symptoms, such as:

Remember, high blood glucose can cause severe complications. If you have any of the symptoms listed above, see your doctor or get medical care right away.

Like most drugs, Opdivo can cause an allergic reaction in some people. Symptoms can be mild or serious and can include:

For mild symptoms of an allergic reaction, such as a mild skin rash or itching, call your doctor right away. They may suggest an over-the-counter oral antihistamine, such as diphenhydramine (Benadryl), or a topical product, like hydrocortisone cream, to manage your allergic reaction.

If your doctor confirms you had a mild allergic reaction to Opdivo, theyll decide if you should continue receiving this drug.

If you have symptoms of a severe allergic reaction, such as swelling or trouble breathing, call 911 or your local emergency number right away. These symptoms could be life threatening and require immediate medical care.

If your doctor confirms you had a serious allergic reaction to Opdivo, theyll stop your Opdivo treatment and decide if another cancer treatment is right for you.

During your Opdivo treatment, consider keeping notes on any side effects youre having. Then, you can share this information with your doctor. This is especially helpful to do when you first start taking new drugs or using a combination of treatments.

Your side effect notes can include things like:

Sharing such notes with your doctor will help your doctor learn more about how Opdivo affects you. Your doctor can also use this information to adjust your treatment plan if needed.

Opdivo may not be right for you if you have certain medical conditions or other factors that affect your health. Talk with your doctor about your health history before starting Opdivo. Factors to consider include those mentioned below.

Stem cell or organ transplant. Opdivo treatment before or after an allogenic hematopoietic stem cell transplant (transplant of blood-forming cells from a genetic match) could cause serious or fatal problems.

If youre planning a stem cell transplant or have had one, talk with your doctor about the safety of Opdivo treatment. Also tell your doctor if youve received an organ transplant.

Allergic reaction. If youve had an allergic reaction to Opdivo or any of its ingredients, Opdivo shouldnt be part of your cancer treatment. Ask your doctor what other medications are better options for you.

Immune system problems. With Opdivo treatment, your immune system may attack healthy tissues.

Before starting Opdivo, tell your doctor if you have an autoimmune or inflammatory condition, such as Crohns disease, ulcerative colitis, or lupus. Tell them even if your condition is in remission (times when youre symptom-free).

History of chest radiation. Opdivo may cause a serious side effect of the lungs called pneumonitis. Your risk for pneumonitis may be higher if youve had radiation treatment to your chest.

Before starting Opdivo, tell your doctor about any past chest radiation treatments youve had and if youve received other drugs similar to Opdivo.

Nervous system problems. In rare cases, Opdivo treatment may cause your immune system to attack your nervous system, including your brain, spinal cord, or nerves.

Before starting Opdivo, tell your doctor if youve had a condition that affects your nervous system, such as myasthenia gravis or Guillain-Barr syndrome.

Opdivo doesnt interact with alcohol.

However, alcohol can harm your liver. In rare cases, Opdivo can cause inflammation (swelling and damage) of your liver known as hepatitis. Opdivo can be used to treat some liver cancers.

Ask your doctor if its safe to consume alcohol while being treated with Opdivo.

Its unsafe to be treated with Opdivo during pregnancy. If youre able to become pregnant, youll need to get a pregnancy test before starting Opdivo to make sure youre not pregnant.

Youll also need to use effective birth control during treatment and for at least 5 months after your last infusion.

Opdivos manufacturer hasnt given recommendations about contraception for people taking Opdivo who have a partner who can become pregnant. If you have questions or concerns about this, talk with your doctor.

Its unknown if Opdivo is safe to use while breastfeeding. You shouldnt breastfeed during Opdivo treatment or for at least 5 months after your last infusion.

Before starting Opdivo, talk with your doctor about safe ways to feed your child.

Opdivo may help treat your type of cancer. At the same time, it can put you at risk for rare but serious side effects. However, most common symptoms of Opdivo are mild or manageable.

If youre wondering about Opdivos side effects, talk with your doctor or pharmacist. Ask questions to get the answers you need to feel confident about your cancer treatment. Here are a few to get you started:

My doctor said thyroid problems are possible serious side effects of Opdivo. What symptoms should I watch for?

Opdivo may cause your immune system to attack your thyroid gland, resulting in thyroiditis (inflammation of the thyroid gland). Though thyroiditis isnt usually serious, it can lead to hypothyroidism (low thyroid levels) or hyperthyroidism (high thyroid levels).

Hypothyroidism may happen more often, especially when Opdivo is used with ipilimumab (Yervoy).

Symptoms of hypothyroidism include increased weight, fatigue (lack of energy), and feeling cold. They also include a slow heart rate, depression, and a puffy face.

Symptoms of hyperthyroidism include a fast heart rate, high blood pressure, shaking hands, and trouble sleeping.

Call your doctor if you have any of the above symptoms. They may pause or stop your Opdivo treatment depending on how severe the side effect is. Your doctor may also recommend that you take other medication to treat your hypothyroidism or hyperthyroidism.

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Opdivo Side Effects: What They Are and How to Manage Them - Healthline

Skin Stem Cells Comments Off on Opdivo Side Effects: What They Are and How to Manage Them – Healthline | January 29th, 2021

Scientists have identified a protein that can slow or stop some signs of Parkinsons disease in mice.

The team found that the bone morphogenetic proteins 5 and 7 (BMP5/7) can have these effects in a mouse model of the disease.

This research, which appears in the journal Brain, may be the first step toward developing a new treatment for Parkinsons disease.

This type of brain disorder typically affects people over the age of 60, and the symptoms worsen with time.

Common symptoms include stiffness, difficulty walking, tremors, and trouble with balance and coordination.

The disease can also affect the ability to speak and lead to mood changes, tiredness, and memory loss.

Parkinsons Foundation report that about 1 million people in the United States had the disease in 2020, with about 10 million affected globally.

Despite this prevalence, scientists are still unsure why Parkinsons disease affects some people and not others, and there is currently no cure.

The National Institute on Aging note that some cases of Parkinsons disease seem to be hereditary. In other words, the disease can emerge in different generations of a family but for many people with the disease, there appears to be no family history.

Researchers believe that multiple factors may affect a persons risk, including genetics, exposure to environmental toxins, and age.

Since there is currently no cure for Parkinsons disease, treatments typically focus on alleviating its symptoms.

Existing treatments can help alleviate of Parkinsons disease, such as stiffness. However, they may work less well, or not work, for others, such as tremors or a loss of coordination.

Though researchers are still unsure why some develop the disease and others do not, they understand what occurs in the brain of a person with Parkinsons.

The disease causes the neurons in the part of the brain that controls movement to stop working or die. The brain region, therefore, produces less of the chemical dopamine, which helps a person maintain smooth, purposeful movement, as the National Institute of Neurological Disorders and Stroke observe.

Also, Lewy bodies occur in the brains of some people with Parkinsons disease. These bodies are clumps primarily made up of misfolded forms of the protein alpha-synuclein.

In their recent study paper, the scientists refer to research suggesting that neurotrophic factors molecules that help neurons survive and thrive could, in theory, restore the function of neurons that produce dopamine. However, the clinical benefit of these factors had yet to be proven.

The team focused on bone morphogenetic proteins 5 and 7 (BMP5/7). They had previously shown that BMP5/7 has an important role in dopamine-producing neurons in mice.

In the latest study, the scientists wanted to see whether BMP5/7 could protect the neurons of mice against the damaging effects of misfolded alpha-synuclein proteins.

To do this, they injected one group of mice with a viral vector that caused misfolded alpha-synuclein proteins to form in their brains. They used other mice as a control group. The scientists then injected the mice with the BMP5/7 protein.

The researchers found that the BMP5/7 protein had a significant protective effect against the misfolded alpha-synuclein proteins.

According to senior study author Dr. Claude Brodski, of the Israel-based Ben-Gurion University of the Negevs Department of Physiology and Cell Biology, We found that BMP5/7 treatment can, in a Parkinsons disease mouse model, efficiently prevent movement impairments caused by the accumulation of alpha-synuclein and reverse the loss of dopamine-producing brain cells. He continues:

These findings are very promising, since they suggest that BMP5/7 could slow or stop Parkinsons disease progression. Currently, we are focusing all our efforts on bringing our discovery closer to clinical application.

The universitys technology transfer company, BGN Technologies, is currently looking to bring the development to the market.

Dr. Galit Mazooz-Perlmuter, the companys senior vice president of bio-pharma business development, notes that There is a vast need for new therapies to treat Parkinsons disease, especially in advanced stages of the disease.

Dr. Brodskis findings, although still in their early stages, offer a disease-modified drug target that will address this devastating condition. We are now seeking an industry partner for further development of this patent-pending invention.

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Protein identified that may help treat Parkinsons disease - Medical News Today

Skin Stem Cells Comments Off on Protein identified that may help treat Parkinsons disease – Medical News Today | January 29th, 2021

Lets get into the science behind it: As hair is being formed, melanocytes inject pigment into keratinocytesthe cells containing keratinwhich is the protein making up hair, skin and nails, says Wayne, NJ plastic surgeon and hair specialist Jeffrey B. Wise, MD. Over time, melanocytes continue to inject pigment into the hairs keratin, which is where hair gets its color. In the aging process, melanocytes slow down and eventually stop secreting melanin, which causes a lack of pigment, and the hair turns gray.

According to Chicago dermatologist Dr. Quenby Erickson, going gray is programmed in our genetic code, which means we can get clues as to how extensively and when it will happen by looking at our parents. However, a 2020 study published in Science Daily shows there may also be a link between stress and gray hair. When testing on mice, researchers found that the type of nerve involved in the fight-or-flight response causes permanent damage to the pigment-regenerating stem cells in the hair follicle. The study makes perfect sense, says Dr. Wise. Stress is a huge factor in premature aging, as well as hair thinning. Naturally, it should also affect hair graying as well. There is also a lot of evidence that shows smoking cigarettes plays a role in making hair go gray earlier.

Color isnt always the only factor either; textural changes can ensue as well. Some people are blessed with gorgeous gray hair, but for most of us, the gray is accompanied with thinning and rougher texture that leave our hair finer and harder to style, Dr. Erickson says. There are no proven ways to prevent hair from turning gray, but both Drs. Erickson and Wise have seen some promising results from platelet-rich plasma (PRP) injections. Because these treatments are aimed at waking up your own stem cells, they could potentially reinvigorate melanocyte production as well, explains Dr. Wise. We have seen growth of darker, thicker hairs on some of our stem cell therapy patients, even though the original goal was to combat thinning. Treatment results are dependent on the patients individual conditions, so realistic expectations should be set by your doctor.

Celebrity colorists Chad Kenyon and Rita Hazan say none of their clients embraced their grays during quarantine, or they tried, but caved eventually. For those in camp cover them up, topical dyes and root concealers can help camouflage. The process to cover gray hair is the same on both blonds and darker shades, but my clients with lighter hair can go longer in between touch-ups because gray hairs blend with blond hairs more easily, says Kenyon. Celebrity colorist Aura Friedman often suggests adding a darker pepper tone to silver hair for people who feel more comfortable being darker, but dont want the two-, three- or four-week regrowth touch-up thats needed.

For those who want to permanently cover their grays at home, Nikki Lee, celebrity colorist and cofounder of Nine Zero One Salon, recommends Garnier Nutrisse Nourishing Color Creme ($8). There are more than 75 shades and you can easily find your match using a virtual shade selector, she says. If DIY color makes you nervous, temporary root sprays are great to use in between salon appointments.

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Why Hair Goes Gray, and How to Cover It If You Want To - NewBeauty Magazine

Skin Stem Cells Comments Off on Why Hair Goes Gray, and How to Cover It If You Want To – NewBeauty Magazine | January 29th, 2021

The International Society for Stem Cell Research (ISSCR) will present this years ISSCR Momentum Award to Valentina Greco, PhD, Carolyn Walch Slayman Professor of Genetics and member of the Yale Stem Cell Center. The prize recognizes the exceptional achievements of an investigator whose innovative research has established a major area of stem cell-related research with a strong trajectory for future success. Greco will present her science during a special lecture on June 25 during ISSCR 2021 Virtual, the worlds leading meeting of global innovators in stem cell science and regenerative medicine.

Studies from Grecos lab are redefining scientific understanding of the complex mechanisms that organize and regulate the skin stem cell niche and the behavior of normal and mutant cells in the epidermis under physiologic challenge and with aging. Her groups body of work exploring cell biology in vivo determined that the niche, rather than the stem cells, are required for tissue growth, that location in the niche dictates stem cell fate, that the niche exploits stem cell plasticity to maintain homeostasis, and that homeostatic correction battles disease emergence. These breakthroughs pave the way for new concepts in mammalian regenerative biology.

Valentina is a wonderful ambassador for the stem cell community and in particular for young, female scientists in our field, said Christine Mummery, PhD, ISSCRs president. She has a confidence and skill to pursue bold new ideas. Not only is she a pioneer in live cell imaging, but she also has made multiple important discoveries regarding the mechanisms that regulate epithelial stem cell function. We are honored to recognize Valentina for her momentous achievements.

Beyond her creativity and scientific talent, Greco has shown great leadership. She is deliberate in her commitment to career development and the training of young faculty and her lab members, and brings tremendous enthusiasm to her work. Throughout her career, Greco has sought out new ways to enhance her effectiveness as a mentor by pursuing education from others, thereby establishing a strong foundation for making fundamental scientific discoveries in partnership with her lab members. She shared her perspectives and experiences as a woman and an immigrant working in science in Stem Cell Reports, Women in Stem Cell Science, Part 1.

My lab and I are honored to be recognized with this award, Greco said. Our science is inspired by the previous insights of incredible scientists that have paved the way for our contributions including the inspiring work of Cristina Lo Celso, David Scadden, Charles Lin, and Shosei Yoshida and their pioneering live imaging of mammalian stem cells in blood regeneration and spermatogenesis.

Greco was also awarded the ISSCR Dr. Susan Lim Outstanding Young Investigator Award in 2014.

Submitted by Robert Forman on January 25, 2021

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Valentina Greco Receives the 2021 ISSCR Momentum Award < Yale School of Medicine - Yale School of Medicine

Skin Stem Cells Comments Off on Valentina Greco Receives the 2021 ISSCR Momentum Award < Yale School of Medicine – Yale School of Medicine | January 27th, 2021

CENTENNIAL, Colo., Jan. 26, 2021 /PRNewswire/ --Essent Biologics, a nonprofit biotechnology company emerging from two years of stealth-mode operation, today announced its launch as a new venture to meet the growing need for human-derived biomaterials and data to the regenerative medicine research community, as well as producing key inputs for further manufacturing by clinical partners.

As a new venture from AlloSource, one of the world's leading manufacturers of fresh cartilage tissue used for joint repair and skin allografts to heal severe burns, Essent Biologics will leverage its connection to human tissue donation by providing low passaged primary cell lines, origin tissue and comprehensive donor data to advance translational research from benchtop to bedside. The company also has the capability to serve as a biomanufacturing partner, creating a large inventory of custom products.

"We are proud to set a new standard in human-derived biomaterials for research," said Corey Stone, Executive Director, Essent Biologics. "Essent will motivate and empower the work researchers are doing by supporting the development of innovative therapies through quality biomaterials and powerful data."

Essent Biologics will supply highly characterized human mesenchymal stem cells (MSCs) produced under current Good Manufacturing Practices (cGMP). The company has already partnered with leading academic research and biopharmaceutical companies who excitedly await Essent Biologics' official product launch, anticipated in April.For additional information on the company's product pipeline, please visit essentbiologics.org.

"The work Essent is doing to help accelerate research through human clinical trials is remarkable," said Ethan Mann, CEO of Validus Cellular Therapeutics, Inc. "We are excited to partner with such an innovative company who will support research to develop new medical solutions, and we look forward to their future growth."

According to Allied Market Research, the Cellular Therapy and Tissue Engineering industries are some of the fastest growing in the regenerative medicine sector. The Cellular Therapy market tallied a total expenditure of $7.25 billion in 2019 and is expected to hit $48.11 billion by 2027. The Tissue Engineering market tallied a total expenditure of $2.3 billion in 2019 and is expected to hit $6.8 billion by 2027. These strong growth rates are powered by an increase in clinical trials and manufacturing throughput.

About Essent BiologicsEssent Biologics is setting a new standard in human-derived biomaterials and 3D biology data for research. The nonprofit biotechnology company provides low passaged primary cells, origin tissue and scaffolds, as well as comprehensive donor and product data to advance regenerative medicine research from benchtop to bedside. Essent Biologics supplies products in small or large volumes and serves as a manufacturing partner by creating master cell banks and an inventory of custom products within a tailored specification. In order to ensure reliable product quality, safety and efficacy, all Essent Biologics products are developed using robust design control processes and produced under current Good Manufacturing Practices (cGMP). For more information, please visit essentbiologics.org.

Media ContactCorey StoneEssent Biologics720.873.4781cstone@essentbiologics.org

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Essent Biologics Launches With A Mission To Provide Human-Derived Biomaterials And 3D Biology Data For Cell Therapy And Tissue Engineering - The Grand...

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Unfortunately, there arent too many manatees that dont have a wound, says Jon (JP) Peterson, vice president of zoological operations at SeaWorld in Orlando, Fla. Peterson oversees the rescue team, a group of wildlife veterinarians and animal specialists who travel the coastal waterways of the Southeast providing emergency medicine to wild animals, including injured, cold and orphaned manatees. Boats are the most common cause of wounds: Sharp skegs and propellers scrape along the animals backs and flanks, leaving behind everything from minor scratches to much more severe lacerations like those Peterson calls sucking chest wounds.

Assess the cut and nearby tissue. Gray is bad, Peterson says. You want pink. If you see dark gray or brown, blood, pus or smell a pungent odor, there is usually infection. A manatees outer skin is tough, like an elephants hide, and prone to close up quickly. Clean, flush and scrub the wound with a sterile solution like chlorhexidine until youve removed the necrotic tissue (you may need to cut it out). To accelerate healing, Petersons team uses antibiotics, cold-laser therapy and stem cells, as well as raw, unpasteurized honey. Use a tongue depressor and pack the honey into the wound, Peterson says. With its sticky, antibacterial properties, honey stays put, even underwater.

Dont underestimate the strength of these animals. Theyre one ball of muscle, Peterson says. Dolphins and whales make less challenging patients. Release healed manatees back into the wild. Of course, unless youre trained and permitted by the U.S. Fish and Wildlife Service, you should not handle manatees at all. Mistreating them is illegal and can result in a fine and prison time. In 1967, only a few hundred manatees remained in Florida when they were listed among the first class of endangered species under the Endangered Species Act. Researchers now estimate the population at 6,300, most with crisscrossing bright white scars across their bodies. In fact, scarring is so prevalent that scientists use scar patterns to identify individual manatees during aerial surveys. You can look down from an airplane and see, Oh, look, theres so-and-so, Peterson says.

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How to Treat a Wounded Manatee - The New York Times

Skin Stem Cells Comments Off on How to Treat a Wounded Manatee – The New York Times | January 27th, 2021

There are lots of places in a skincare routine where a budget product can do the job perfectly well, but your serum often isnt one of them; an effective, affordable serum is a rare thing. Its no wonder, then, that a bottle of The Body Shops brilliant youth concentrate sells every 27 seconds.

The entire Drops of Youth range, of which youth concentrate is one of the stars, is formulated around the same quad of ingredients and, as well as the serum, includes a foaming cleanser, toner, eye cream, moisturiser, night-time mask, sheet mask, reformulated liquid peel and the new bouncy jelly mist.

As part of its launch, a trio of products from the Drops of Youth range the new mist, the reformulated peel and the cult serum have been rebranded for the lockdown age, emphasising their pollution clearing and blue light-fighting properties.

Now we are spending more time indoors than ever, you might expect that our skins exposure to environmental damage is much reduced. But indoor pollution is a problem, too. Confined to our houses, heating, ventilation, cooking, damp, dust and even the light from your phone have the potential to cause surface-level congestion (aka spots) and deep damage, leading to premature ageing and possible discolouration.

High-energy visible light (HEV light), often referred to as blue light are rays emitted from the screens of the devices phones, tablets, laptops on which we increasingly spend our days, and penetrates the skin more deeply than UV rays, in part due to how much closer its source is to our faces than the sun.

We put the new and improved range to the test to see if it lives up to expectations.

You can trust our independent reviews. We may earn commission from some of the retailers, but we never allow this to influence selections, which are formed from real-world testing and expert advice. This revenue helps to fund journalism across The Independent.

Drops of Youth Bouncy Jelly Mist

(The Body Shop)

The Drops of Youth bouncy jelly mist feels wetter and more substantial on first application than many similar hydrating sprays, and quickly absorbs and dries down to a silky, matte finish on the skin. We love it for a mid-afternoon refresh, when our skin is starting to feel dry, though we find the spritz a little too heavy to apply directly to the face, and so prefer to spray it into our hands first. If you want to spray it over make-up, make sure you hold the bottle an arms length away.

The formula contains a trio of plant stem cells: criste marine, sea holly and edelweiss, all of which are known for their resilience and regenerating powers in the wild. Edelweiss, sourced from the Italian Alps, is particularly interesting. The flower survives UV rays and extreme weather where it grows at altitude, and in skincare is a powerful antioxidant.

It contains leontopodic acid, which strengthens the skins barrier, encouraging regeneration and hydration, and reducing and soothing sensitive reactions, thus increasing your skins resistance to external pressures including blue light and indoor pollution.

It also contains fair trade moringa oil, which is itself an excellent source of vitamins and antioxidants, including quercetin and vitamins A, C and E, all of which further the protection against environmental aggressors offered by the Drops of Youth plant stem cell trio. Moringa oil is also a good source of amino acids and oleic acid, a fatty acid that helps restore the skins natural barrier and protects against moisture loss, and is a lighter weight than many other plant oils. Youll find all these ingredients throughout the Drops of Youth range, making it a strong offering for both antioxidant protection and lasting hydration.

(The Body Shop)

The cult youth concentrate serum is, of course, also a favourite. With its pipette applicator, slightly gloopy texture and excellent slip across the skin (a tiny drop goes a long way), it has the application experience of a far more expensive serum. It dries to a slightly tacky finish (which we dont mind, as its rarely the final product in our routine) and feels like a fresh drink for your skin. For those who want a hydrating, protecting serum, it makes a happy two-in-one swap for hyaluronic acid and vitamin C serums, and at a very competitive price point.

Drops of Youth Liquid Peel

(The Body Shop)

Completing the trio is the liquid peel, which has a gel-like consistency and is, curiously, massaged into dry skin. After a few seconds white peelings begin to lift away from the skin; it's quite a dramatic effect and the claim is that this is dead skin lifting away, but at least some of it will be the product itself.

The classic exfoliating ingredient in the peel is citric acid, though it's very low on the ingredients list, meaning it's included in small quantities. Skin is left soft and smooth, and it's a good option for those with sensitive skin or who are scared of the exfoliating heavyweights, but those who are after a more serious peel will find it underwhelming.

Drops Of Youth Eye Concentrate

(The Body Shop)

Another highlight from the range, this has a rolling metal ball applicator and a light, gel-like texture that is more like a serum than a traditional eye cream. It is gorgeously soothing and cooling perfect on tired, irritated eyes and to alleviate morning puffiness and leaves the skin plumped and smooth.

We also love the youth cream moisturiser (25), which again has a light, whipped gel texture and leaves skin plump and silky smooth. Its the perfect base for make-up.

Drops of Youth bouncy sleeping mask

(The Body Shop)

A final favourite is the youth bouncy sleeping mask (22), and not just for the name. We love the promise of night skincare maximum time for the product to work on its skin, minimum effort involved and this is a proper mask that requires rinsing off in the morning, unlike many night-time masks, which feel more like heavy moisturisers. It has a thick, jelly-like texture that you have to really dig into to break the surface; after each unceremonious scoop it magically settles into a smooth, level surface infinitely satisfying. Skin is left brighter, nourished and glowing in the morning.

The verdict: The Body Shop Drops of Youth range

The range is a brilliant choice for skincare addicts after protection from environmental damage and bouncy, hydrated skin without the spend demanded by luxury products. The cult serum, youth concentrate, remains the star of the extended line-up, but your face will reward you for adding the new bouncy jelly mist to your cart, too. Drops of Youth is a bold marketing claim, but the plump, fresh, glowing skin it gives certainly helps.

IndyBest product reviews are unbiased, independent advice you can trust. On some occasions, we earn revenue if you click the links and buy the products, but we never allow this to bias our coverage. The reviews are compiled through a mix of expert opinion and real-world testing.

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We tried The Body Shops new Drops of Youth skincare range heres what we thought - The Independent

Skin Stem Cells Comments Off on We tried The Body Shops new Drops of Youth skincare range heres what we thought – The Independent | January 27th, 2021

A study examining the damage caused to nerve cells by motor neuron disease (MND) has shown that by targeting these cells energy centers, called mitochondria, neuronal function can be restored.

The research, conducted by a team at the University of Edinburgh, has been published in the journal Acta Neuropathologica.1MND is a broad term for a group of rare, progressive and sometimes fatal neurodegenerative conditions, including amyotrophic lateral sclerosis (ALS), progressive bulbar palsy (PBP) and progressive muscular atrophy (PMA).

The research team, led by Dr Arpan Mehta, alongside Dr Bhuvaneish Selvaraj and Professor Siddharthan Chandran, all based at the University of Edinburghs Euan MacDonald Centre for MND Research, focused their work on the axon of human motor neurons. This is the region of a motor neuron that conducts electrical signals released by the brain and carries them to the body part they are intended for. In some human motor neurons, the axon can be over a meter long. These processes are energy-guzzling, and that power is provided by mitochondria, known to generations of long-suffering biology students as the powerhouses of the cell.

The scientists noted that the axons of MND-affected neurons were shorter than normal, and their mitochondria were not as easily able to move around the cell as they were in healthy neurons.

Using stem cells taken from people who have a mutation in a gene called C9orf72 that is known to play a causal role in both the MND subtype ALS and frontotemporal dementia, Mehta and colleagues created a stem cell model of MND, and sought to repair these stricken neurons.

In their stem cell models of MND, the team showed that by increasing the levels of a protein named PGC1 that regulates mitochondrial energy metabolism, the motor neurons function could be returned to healthy levels.

Dr Arpan Mehta (right), alongside Euan MacDonald MBE, co-founder of the Euan MacDonald Centre.

Our data provides hope that by restoring the cells energy source we can protect the axons and their connection to muscle from degeneration. Work is already underway to identify existing licensed drugs that can boost the mitochondria and repair the motor neurons. This will then pave the way to test them in clinical trials.

The team focused solely on the most common genetic form of ALS in their study and acknowledge that MNDs such as ALS are caused by a range of genetic and environmental factors. Nevertheless, they hope that their findings can be applied to other forms of the disease.

Reference:Mehta AR, Gregory JM, Dando O, et al. Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis. Acta Neuropathol. Published online January 4, 2021. doi:10.1007/s00401-020-02252-5

Correction: This article was updated on January 25, 2021 to amend a quote from Dr Mehta.

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Genetic Energy Boost Reverses Cellular Effects of Motor Neuron Disease - Technology Networks

Spinal Cord Stem Cells Comments Off on Genetic Energy Boost Reverses Cellular Effects of Motor Neuron Disease – Technology Networks | January 27th, 2021

Biology Educational Videos

Last Updated on October 12, 2020 by Sagar Aryal

Stem cells are unique cells present in the body that have the potential to differentiate into various cell types or divide indefinitely to produce other stem cells.

Figure: Stem Cell Renewal and Differentiation. Image Source: Maharaj Institute of Immune Regenerative Medicine.

All the stem cells found throughout all living systems have three important properties. These properties can be visualized in vitro by a process called clonogenic assays, where a single cell is assessed for its ability to differentiate.

The following are some properties of stem cells:

Figure: Techniques for generating embryonic stem cell cultures. Image Source: John Wiley & Sons, Inc. (Nico Heins et al.)

Depending on the source of the stem cells or where they are present, stem cells are divided into various types;

Figure: Human Embryonic Stem Cells Differentiation. Image created with biorender.com

Figure: Preliminary Evidence of Plasticity Among Nonhuman Adult Stem Cells. Image Source: NIH Stem Cell Information.

Figure: Progress in therapies based on iPSCs. Image Source: Nature Reviews Genetics (R. Grant Rowe & George Q. Daley).

Figure: Mesenchymal stem cells (MSCs). Image Source: PromoCell GmbH.

Some of the common and well-known examples of stem cell research are:

Stem cell research has been used in various areas because of their properties. Some of the common applications of stem cells research include;

Because of different ethical and other issues related to stem cell research, there are some limitations or challenges of stem cell research. Some of these are:

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Stem Cells- Definition, Properties, Types, Uses, Challenges

Cardiac Stem Cells Comments Off on Stem Cells- Definition, Properties, Types, Uses, Challenges | January 27th, 2021

METUCHEN, N.J., Jan. 25, 2021 /PRNewswire/ -- Tevogen Bio today announced it has secured necessary funding from HMP Partners of New Jersey, an investment firm managed by medical doctors, which will allow Tevogen to support all clinical trials of its investigational, potentially curative COVID-19 treatment. Tevogen's Investigational New Drug (IND) application for its proprietary antigen-specific T cell therapy is under review by the U.S. Food and Drug Administration (FDA).

All COVID-19 therapeutics utilized to date have sought to slow the progression of the infection and/or moderate its symptoms. These approaches buy time for the patient's own T cells to activate and respond to the infection, which is the mechanism that the body employs to rid itself of viruses such as the SARS-CoV-2.

In the upcoming trials, Tevogen will study its investigational treatment, TVGN-489, allogeneic T cells that have been programmed and grown in the laboratory, for its safety and capability to recognize and destroy COVID-19 infected cells. Lead investigator Dr. Neal Flomenberg, Chair of the Department of Medical Oncology at Thomas Jefferson University, stated his optimism, "We're excited by the purity and potency of the cells we've been able to generate in the lab. Based on prior experience with these sorts of cells in other settings, we're very hopeful that they will be both safe and effective when the clinical trials are launched."

HMP Partners is supporting Tevogen's efforts to develop a curative treatment due to concerns over recent COVID-19 mutations and the current lack of curative options for this deadly infection. HMP CEO Dr. Manmohan Patel, a prominent pulmonary and critical care specialist, said, "We believe it's imperative to create a curative treatment that is not expected to be compromised by mutations." He added, "Unmodified virus specific T cells are well established as being effective and safe at treating viral infections, which is why we are supporting Tevogen's efforts to develop a much-needed COVID-19 cure."

While Tevogen has raised private investment from HMP Partners to launch its clinical trials, the company is seeking government funding to expedite capacity to manufacture at the scale necessary to develop pandemic-level product supply, just as have a number of vaccine and antibody manufacturers.

Tevogen's proprietary solution is designed to enable a single donation from a donor to generate more than a thousand doses of COVID-19 specific cytotoxic T cells.Yale-trained infectious disease epidemiologist Dr. Ryan Saadi is leading Tevogen's efforts and is among those who are financing the trials. Dr. Saadi stated, "We halted our pursuit for an oncology cure in order to focus solely on COVID-19, and our manufacturing efficiencyand agile business model will allow us to deliver a cure that will be affordable and accessible to all."

About Tevogen Bio

Tevogen Bio was formed after decades of research by its contributors to concentrate and leverage their expertise, spanning multiple sectors of the healthcare industry, to help address some of the most common and deadly illnesses known today. The company's mission is to provide curative and preventative treatments that are affordable and scalable, in order to positively impact global public health.

About HMP Partners

HMP Partners of New Jersey is a consortium of medical doctors who are dedicated to supporting the advancement of potentially life-saving technologies. HMP CEO Dr. Manmohan Patel, a prominent pulmonary and critical care specialist, has nearly 50 years of medical expertise in a diverse field of specialties, including pulmonary, internal, geriatric and emergency medicine as well as critical care. Dr. Patel's commitment to community and medical management is demonstrated by his distinguished appointments, including serving as the Director of Post Cardiac Surgery at Saint Michael's Medical Center in Newark, NJ and as Chairman of the Department of Medicine at Meadowlands Hospital Medical Center in Secaucus, NJ. In 2000, he was appointed by the Governor of New Jersey to the Board of Medical Examiners Executive Committee for the state and served on various other committees, including reviewing malpractice actions, in that capacity.

About Dr. Neal Flomenberg

Dr. Neal Flomenberg is the Chairman of the Department of Medical Oncology and Deputy Director of the Sidney Kimmel Cancer Center at Jefferson University in Philadelphia.Dr. Flomenberg launched Jefferson's Blood and Marrow Transplantation (BMT) Program in 1995. Throughout his four decades of practice, he has maintained a longstanding interest in the immunogenetics and immunology of stem cell transplantation, with the goal of making transplantation safer and more widely available. He is board certified in the fields of internal medicine, hematology, and medical oncology.

Media Contacts:

Mark Irion

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Katelyn Petroka[emailprotected]

SOURCE Tevogen Bio

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Tevogen Bio Secures Funding from Team of Doctors to Support Clinical Trials of Its Investigational Curative T Cell Therapy for COVID-19 - PRNewswire

Cardiac Stem Cells Comments Off on Tevogen Bio Secures Funding from Team of Doctors to Support Clinical Trials of Its Investigational Curative T Cell Therapy for COVID-19 – PRNewswire | January 27th, 2021

'Every day that passes is a huge success' for the parents of a little boy who has received a life-saving stem cell transplant.

Zakk Galvin battled leukaemia for 18 months, but after his chemotherapy treatment stopped being effective, his parents were forced to appeal for a stem cell donor.

He has been offered a new lease of life after the transplant has gone ahead.

The six-year-old from Winterton is currently in a fragile condition recovering from the transplant in hospital.

It took months of searching to find a matching donor for Zakk odds that his parents compared to one in a million.

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Zakk has been staying in Sheffield Childrens Hospital since the process began on Boxing Day. It could be months until he can return home, but his parents are thankful for each day.

Dad Craig said: The first week was spent preparing Zakk to receive the cord blood transplant which involved a significant amount of chemotherapy and total body irradiation therapy.

The purpose of this was to totally eliminate any remaining cancer from his body, as well as dampen his body's natural instinct to fight anything invading.

This made Zakk very poorly, and indeed we had some of our hardest days and nights since his journey began in March 2019.

Along with this was the fragility that comes with such treatment, as his immune system and own body defences must be completely overcome in order for the grafted stem cells to not be rejected.

Zakk, who lives in Winterton, has acute lymphoblastic leukaemia, a rare form in which the bone marrow produces faulty white blood cells.

On January 4, he received the healthy stem cells which can take over.

Bone marrow is the tissue inside of bones.

It's a 'factory' which it essential to the human body, as it produces all the required blood cells.

However, it can stop working properly due to diseases like leukemia.

In these cases, the best hope is a transplant from someone with healthy bone marrow.

The actual transplant itself went ahead relatively anti-climactically, Craig said.

You would think that this monumental occasion would involve a huge theatre surgery or some fantastical machine, when in actual fact it is an IV infusion over within about 45 minutes.

But God is in the detail because what was being infused was the stem cells which would hopefully implant and give Zakk new life.

The young boy is now undergoing a vigorous schedule of daily tests and scans to monitor his health.

Due to his fragile condition, he isnt able to see his mum Elizabeth or sisters Annabelle and Eshter, who are eagerly waiting for his return home.

He is very tired, very irritable and suffering from any number of unpleasant symptoms, but we pray that through this trial a miracle is happening just waiting to break through, Craig said.

We know, and most importantly he knows, that it will be a rollercoaster ride, that tonight maybe totally different from today, tomorrow a stark contrast to yesterday.

"But still we look to the day when he will be able to leave hospital and come home to see his sisters, mother and cats.

He's too fragile to be able to see them until that time. We don't know at this time when that will be, his birthday is in late March - it would be wonderful for him to have it at home!

As his transplant consultant has said, Every day that passes is a huge success so we must thank the Lord for every day.

To help other people in urgent need of a donor, you can join the British Bone Marrow Registry or register with the DKMS .

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Every day is a success for little boy with leukaemia after life-saving transplant - Grimsby Live

Bone Marrow Stem Cells Comments Off on Every day is a success for little boy with leukaemia after life-saving transplant – Grimsby Live | January 27th, 2021

As public demand grows for limited supplies of covid-19 vaccines, questions remain about the vaccines appropriateness for older adults with various illnesses. Among them are cancer patients receiving active treatment, dementia patients near the end of their lives and people with autoimmune conditions.

Recently, a number of readers have asked me whether older relatives with these conditions should be immunized. This is a matter for medical experts, and I solicited advice from several. All strongly suggested that people with questions contact their doctors and discuss their individual medical circumstances.

Experts advice may be helpful since states are beginning to offer vaccines to adults over age 65, 70 or 75, including those with serious underlying medical conditions. Twenty-eight states are doing so, according to the latest survey by The New York Times.

Q: My 80-year-old mother has chronic lymphocytic leukemia. For weeks, her oncologist would not tell her yes or no about the vaccine. After much pressure, he finally responded: It wont work for you, your immune system is too compromised to make antibodies. She asked if she can take the vaccine anyway, just in case it might offer a little protection, and he told her he was done discussing it with her.

First, some basics. Older adults, in general, responded extremely well to the two covid-19 vaccines that have received special authorization from the Food and Drug Administration. In large clinical trials sponsored by drugmakers Pfizer and Moderna, the vaccines achieved substantial protection against significant illness, with efficacy for older adults ranging from 87% to 94%.

But people 65 and older undergoing cancer treatment were not included in these studies. As a result, its not known what degree of protection they might derive.

Dr. Tobias Hohl, chief of the infectious diseases service at Memorial Sloan Kettering Cancer Center in New York City, suggested that three factors should influence patients decisions: Are vaccines safe, will they be effective, and what is my risk of becoming severely ill from covid-19? Regarding risk, he noted that older adults are the people most likely to become severely ill and perish from covid, accounting for about 80% of deaths to date a compelling argument for vaccination.

Regarding safety, there is no evidence at this time that cancer patients are more likely to experience side effects from the Pfizer-BioNTech and Moderna vaccines than other people. Generally, we are confident that these vaccines are safe for [cancer] patients, including older patients, said Dr. Armin Shahrokni, a Memorial Sloan Kettering geriatrician and oncologist.

The exception, which applies to everyone, not just cancer patients: people who are allergic to covid-19 vaccine components or who experience severe allergic responses after getting a first shot shouldnt get covid-19 vaccines.

Efficacy is a consideration for patients whose underlying cancer or treatment suppresses their immune systems. Notably, patients with blood and lymph node cancers may experience a blunted response to vaccines, along with patients undergoing chemotherapy or radiation therapy.

Even in this case, we have every reason to believe that if their immune system is functioning at all, they will respond to the vaccine to some extent, and thats likely to be beneficial, said Dr. William Dale, chair of supportive care medicine and director of the Center for Cancer Aging Research at City of Hope, a comprehensive cancer center in Los Angeles County.

Balancing the timing of cancer treatment and immunization may be a consideration in some cases. For those with serious disease who need therapy as quickly as possible, we should not delay [cancer] treatment because we want to preserve immune function and vaccinate them against covid, said Hohl of Memorial Sloan Kettering.

One approach might be trying to time covid vaccination in between cycles of chemotherapy, if possible, said Dr. Catherine Liu, a professor in the vaccine and infectious disease division at Fred Hutchinson Cancer Research Center in Seattle.

In new guidelines published late last week, the National Comprehensive Cancer Network, an alliance of cancer centers, urged that patients undergoing active treatment be prioritized for vaccines as soon as possible. A notable exception: Patients whove received stem cell transplants or bone marrow transplants should wait at least three months before getting vaccines, the group recommended.

The American Cancer Societys chief medical and scientific officer, Dr. William Cance, said his organization is strongly in favor of cancer patients and cancer survivors getting vaccinated, particularly older adults. Given vaccine shortages, he also recommended that cancer patients who contract covid-19 get antibody therapies as soon as possible, if their oncologists believe theyre good candidates. These infusion therapies, from Eli Lilly and Co. and Regeneron Pharmaceuticals, rely on synthetic immune cells to help fight infections.

Q: Should my 97-year-old mom, in a nursing home with dementia, even get the covid vaccine?

The federal government and all 50 states recommend covid vaccines for long-term care residents, most of whom have Alzheimers disease or other types of cognitive impairment. This is an effort to stem the tide of covid-related illness and death that has swept through nursing homes and assisted living facilities 37% of all covid deaths as of mid-January.

The Alzheimers Association also strongly encourages immunization against covid-19, both for people [with dementia] living in long-term care and those living in the community, said Beth Kallmyer, vice president of care and support.

What I think this question is trying to ask is Will my loved one live long enough to see the benefit of being vaccinated? said Dr. Joshua Uy, medical director at a Philadelphia nursing home and geriatric fellowship director at the University of Pennsylvanias Perelman School of Medicine.

Potential benefits include not becoming ill or dying from covid-19, having visits from family or friends, engaging with other residents and taking part in activities, Uy suggested. (This is a partial list.) Since these benefits could start accruing a few weeks after residents in a facility are fully immunized, I would recommend the vaccine for a 97-year-old with significant dementia, Uy said.

Minimizing suffering is a key consideration, said Dr. Michael Rafii, associate professor of clinical neurology at the University of Southern Californias Keck School of Medicine. Even if a person has end-stage dementia, you want to do anything you can to reduce the risk of suffering. And this vaccine provides individuals with a good deal of protection from suffering severe covid, he said.

My advice is that everyone should get vaccinated, regardless of what stage of dementia theyre in, Rafii said. That includes dementia patients at the end of their lives in hospice care, he noted.

If possible, a loved one should be at hand for reassurance since being approached by someone wearing a mask and carrying a needle can evoke anxiety in dementia patients. Have the person administering the vaccine explain who they are, what theyre doing and why theyre wearing a mask in clear, simple language, Rafii suggested.

Q: Im 80 and I have Type 2 diabetes and an autoimmune disease. Should I get the vaccine?

There are two parts to this question. The first has to do with comorbidities having more than one medical condition. Should older adults with comorbidities get covid vaccines?

Absolutely, because theyre at higher risk of becoming seriously ill from covid, said Dr. Abinash Virk, an infectious diseases specialist and co-chair of the Mayo Clinics covid-19 vaccine rollout.

Pfizers and Modernas studies specifically looked at people who were older and had comorbidities, and they showed that vaccine response was similar to [that of] people who were younger, she noted.

The second part has to do with autoimmune illnesses such as lupus or rheumatoid arthritis, which also put people at higher risk. The concern here is that a vaccine might trigger inflammatory responses that could exacerbate these conditions.

Philippa Marrack, chair of the department of immunology and genomic medicine at National Jewish Health in Denver, said theres no scientifically rigorous data on how patients with autoimmune conditions respond to the Pfizer and Moderna vaccines.

So far, reasons for concern havent surfaced. More than 100,000 people have gotten these vaccines now, including some who probably had autoimmune disease, and theres been no systematic reporting of problems, Marrack said. If patients with autoimmune disorders are really worried, they should talk with their physicians about delaying immunization until other covid vaccines with different formulations become available, she suggested.

Last week, the National Multiple Sclerosis Society recommended that most patients with multiple sclerosis another serious autoimmune condition get the Pfizer or Moderna covid vaccines.

The vaccines are not likely to trigger an MS relapse or to worsen your chronic MS symptoms. The risk of getting COVID-19 far outweighs any risk of having an MS relapse from the vaccine, it said in a statement.

Were eager to hear from readers about questions youd like answered, problems youve been having with your care and advice you need in dealing with the health care system. Visitkhn.org/columniststo submit your requests or tips.

Judith Graham: khn.navigatingaging@gmail.com,@judith_graham

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If I Have Cancer, Dementia or MS, Should I Get the Covid Vaccine? - Kaiser Health News

Bone Marrow Stem Cells Comments Off on If I Have Cancer, Dementia or MS, Should I Get the Covid Vaccine? – Kaiser Health News | January 27th, 2021

Background

Acute myeloid leukemia (AML) remains the most common acute leukemia in adults with an incidence of 34 per 100,000 person per year. AML is a genetically and phenotypically heterogeneous and biologically dynamic spectrum of diseases.1 Indeed, the clinical outcomes are largely determined by the patients characteristics such as age, performance status and comoridities, as well as the leukemia features including the subtype (de novo versus secondary) and most importantly the genomic profile.2 The recent advances in defining the molecular landscape of AML and its role in leukemogenesis have paved the way for the development and adaptation of novel targeted agents.

Following induction chemotherapy, patients achieving a morphologic leukemia-free state (complete remission (CR)) are mandated to receive a form of consolidation therapy aimed at the residual leukemic stem cells (LSCs) to prevent relapse and improve overall survival (OS).3 A risk-adapted approach for relatively young or fit AML patients in first CR (CR1) involves the assessment of this risk of relapse, leading to either chemotherapy continuation or allogeneic stem cell transplantation (ASCT), taking into account the presence of comorbidities, the donor type as well as the genetic characteristics of the disease.4 In addition to pre-treatment risk stratification, the estimation of the leukemic burden while on therapy has recently emerged as a strong, independent and dynamic tool for individualizing post-induction treatment approaches. Either polymerase chain reaction (PCR), multiparameter flow cytometry (MFC) or the novel next-generation sequencing (NGS) can evaluate this measurable residual disease (MRD)57

Up to the current date, ASCT in first CR remains the most powerful antileukemic post-remission therapy. ASCT is generally recommended upfront for properly selected patients with high-risk cytogenetic features, those with intermediate and adverse-risk molecular findings, and patients with secondary AML. Patients with induction failure, post-induction residual disease and following salvage therapy are also referred for ASCT. In addition to potentially life-threatening complications of ASCT such as graft-versus-host disease (GVHD) and opportunistic infections, survival benefits recorded with ASCT are crippled by unacceptably high disease relapse rates,810 hence the need for strategies to maintain remission and prevent relapses post-ASCT. Such interventions aim at reinforcing the graft-versus-leukemia (GVL) effect and/or eradicating persistent MRD, especially with the increasing availability of more sensitive techniques to detect any residual disease. Nevertheless, these maintenance therapies may represent over-treatment for patients with intermediate-risk disease, further subjecting them to long-term toxicities and disturbed quality of life (QoL), thereby reinforcing the need for a better selection of patients as well as strict and continuous MRD monitoring.

The transplantation field has tremendously evolved over the last two decades with refinements of indications as well as improvement in the safety profile of conditioning regimens and supportive care strategies. Nonetheless, risk factors for increasing mortality after relapse in an allografted patient still include, among others, a shorter time to recurrence and occurrence of GVHD prior to relapse11 with significant improvement of overall survival (OS) for young patients relapsing in recent years (Bazarbachi et al, 2020).12 Furthermore, a deeper understanding of factors facilitating disease relapse, such as molecular profile and role of MRD, has enabled more high-risk patients to receive post-transplant therapies to treat and even prevent relapses. Indeed, pharmacological intervention and manipulation of the disease kinetics in the early post-transplant phase could potentially collaborate with other strategies to improve overall outcomes,13 possibly through up-regulation of tumor-associated antigens (TAA),14 expansion of regulatory T-cells,15 or acceleration of T-cell reconstitution.16 With the availability of a wide array of novel and less toxic agents such as epigenetic modifiers, tyrosine kinase inhibitors (TKIs), BCL2 inhibitors and immune checkpoint inhibitors (ICPIs) among others, an intriguing strategy would be to preemptively use such molecules in an attempt to prevent relapses post-ASCT in specific subsets of high-risk patients. Nevertheless, we currently only have few randomized trials that offered a survival advantage for maintenance therapy in AML.

Conducting either retrospective studies or prospective randomized trials to construct therapeutic strategies aiming at reducing post-ASCT relapse rates has been historically hampered by the depth of remission achieved as well as the intrinsic biologic apparatus of the disease. Cytogenetic abnormalities of AML knowingly dictate both the general outcomes of standard therapies and those following ASCT.17 In view of the granular advances in the field of myeloid malignancies, considering specific subsets of AML patients for post-ASCT maintenance should therefore depend on the molecular and genomic characteristics of the disease itself at diagnosis.18 Indeed, the presence of actionable or targetable mutations such as FLT3-ITD and IDH1/2 is a valuable opportunity to incorporate the approved corresponding inhibitors in the post-ASCT maintenance strategies. Novel molecular and MRD diagnostics are therefore of utmost importance to determine those who would benefit the most from personalized therapy options. As such, MRD status in the pre-transplant phase and more importantly detection of MRD early post-ASCT are crucial factors to implement therapy as they largely impact the likelihood and pace of disease relapse.19,20

In this setting, other variables including the donor source, intensity of conditioning regimen and GVHD prophylaxis protocols (T-cell depletion and post-ASCT cyclophosphamide) might influence the risk of disease relapse.21 While the implementation of reduced-intensity conditioning (RIC) has allowed more patients to receive ASCT,22 it could potentially increase the rate of post-transplant relapse, as demonstrated by the large prospective randomized Phase III trial conducted by the Bone Marrow Transplant Clinical Trials Network.23 Well-designed trials are eagerly needed to appropriately answer these challenging situations.

In the presence of few prospective randomized trials, the decision to initiate post-ASCT maintenance therapy remains ambivalent in many situations. Early-phase studies assessing novel agents in the relapsed setting often exclude patients with prior history of ASCT given the plethora of complications they might experience, therefore resorting to agents previously approved for different indications or settings. This dilemma largely provides a protective blanket to access these drugs on an off-label indication, which could impede recruitment for prospective studies. Additionally, most currently ongoing maintenance trials using hypomethylating agents (HMA), targeted therapies and other molecules still demand rigorous eligibility criteria, thereby interfering with enrollment rate.

Starting maintenance therapy in the early post-ASCT phase should take into account the concomitant use of immunosuppressive drugs and their potential heightened hematological and organ toxicities, the risk of opportunistic infections and GVHD, as well as the possible drugdrug interactions (such as with calcineurin inhibitors), even when the acute toxicities of ASCT have seemingly resolved. An optimal maintenance approach is therefore difficult to be intercalated within the conditioning regimen itself and is reserved for a post-ASCT phase, mostly started between days 30 and 100 following transplantation. In this setting, pre- and post-ASCT MRD status could be valuable in planning and timing maintenance therapy. For those patients with impending signs of relapse by MRD testing or falling donor chimerism, a preemptive maintenance therapy could be started early post-ASCT, before overt morphological relapse.

Finally, the optimal duration of maintenance therapy has not been established for most cases, thereby affecting the QoL of these patients.

The use of HMAs such as azacitidine and decitabine remains the most commonly adopted non-targeted strategy for the prevention of post-ASCT relapse owing in part to their acceptable safety profile.24 The mechanism of action of HMAs post-ASCT is unclear, but they appear to silence tumor suppressor genes through epigenetic modification. At the preclinical level, these agents could also induce a GVL effect through stimulation of CD8+ T-cell responses to overexpressed tumor-associated antigens (TAAs) such as MAGE antigens.25 This activity has led to the investigation of HMAs in a series of small trials, especially with the advancing field of MRD detection by sensitive techniques.

For example, AML patients with imminent relapse due to decreasing CD34 chimerism received pre-emptive azacitidine that delayed disease progression according to two studies.26,27 The concurrent administration of donor lymphocyte infusion (DLI) did not, however, improve response rates or OS27 and the majority of patients eventually experienced overt disease relapse.26 In another study, azacitidine was also given sequentially with DLI and showed a low relapse rate and encouraging OS despite the presence of acute and chronic GVHD.28

In a Phase I dose-finding trial, azacitidine as monotherapy was given between on day +42 post-ASCT to 45 patients with AML (82%) and MDS, for up to four cycles at different dose levels 8, 16, 24, 32, and 40 mg/m2.29 Interestingly, two-thirds of AML patients were not in CR at the time of transplant. The recommended dose of azacitidine was reported to be 32 mg/m2 for 5 days in 30-day cycles because of dose-limiting but reversible thrombocytopenia. At 1-year follow-up, the median disease-free survival (DFS) was 58% for all enrolled patients and the 1-year OS rate was 77%. In another phase I/II study of 27 AML patients who received a RIC regimen followed by ASCT later showed that the subcutaneous administration of up to 10 cycles of azacitidine at 36 mg/m2 for 5 days in 28-day cycles beginning at day 42 post-ASCT resulted in the expansion of circulating regulatory T-cells with subsequent GVL response and no significant GVHD.15 In a retrospective study of 18 allografted patients (13 AML and 5 MDS), including 50% of patients with a high or very high disease risk index, low-dose azacitidine started at a median of 60 days post-transplant was well tolerated and resulted in one-year disease-free survival (DFS) and OS of 63% and 70%, respectively.30 A subsequent randomized phase III trial comparing azacitidine at 32 mg/m2 subcutaneously for 5 days in up to 12, 28-day cycles to no intervention in 87 patients with AML, myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia in remission was terminated early because of slow accrual.31 At a median follow-up of 4.6 years in the azacitidine arm, available data suggest no significant effect of the HMA on relapse-free survival (RFS), except for a non-statistically significant trend for improvement in those who received at least 9 cycles of therapy.

The importance of MRD-adapted therapy is highlighted in the ongoing Phase II study (RELAZA2) whereby preemptive treatment with at least 6 cycles of azacitidine (75 mg/m2 7 days) and for up to 18 additional months was evaluated.32 The study enrolled patients in CR but with detectable MRD either after conventional chemotherapy or following ASCT. This preemptive MRD risk-adapted strategy was found to prevent or significantly delay disease relapse in 58% of patients who remained in CR after 6 months (95% CI: 4472; p < 0.001). These results are encouraging and warrant further follow-up.

More recently, an oral azacitidine formulation CC-486 with extended dosing to prolong activity of azacitidine with sustained DNA hypomethylation showed promising results as maintenance therapy in a randomized trial following induction chemotherapy for AML.33 CC-486 was then evaluated in a phase I/II trial of 30 patients (26 with AML and 4 MDS) who had undergone ASCT, given at 200300 mg orally for 7 days or 150200 mg orally for 14 days in up to 12, 28-day cycles.34 The study resulted in 1-year RFS rates of 54% with the 7-day protocol and 72% with the 14-day regimen in the 28 evaluable patients, leading to estimated 1-year survival rates of 86% and 81%, respectively. The most common grade 34 treatment-related toxicities were gastrointestinal and hematologic toxicities, and two patients experienced severe chronic GVHD. A randomized, phase III trial evaluating CC-486 at the 200 mg 14-day dosing regimen as maintenance therapy post-ASCT for high-risk MDS and intermediate- or high-risk AML is currently enrolling.

On the other hand, a small study of decitabine administered at 515 mg/m2 intravenously for 5 days starting 50100 days post ASCT for up to 8, 6-week cycles also exhibited favorable results with 2-year OS of 56% and cumulative incidence of relapse reaching 28%.35 However, the majority (75%) of patients experienced grade 34 hematologic toxicities during therapy. While decitabine did not increase the rate of chronic GVHD, there was a trend for increased FOXP3 expression and T-reg cells in the lymphocyte environment in a correlative study that was not statistically meaningful.

Interpreting the results of these studies remains challenging and controversial, as they are small and mostly uncontrolled. As such, the optimal timing of HMA initiation post-ASCT and dosing need to be explored further to establish efficacy at preventing relapses and avoid unnecessary toxicities, especially in patients who can be cured with ASCT alone. In patients with detectable MRD or mixed chimerism, pre-emptive treatment with HMA could potentially delay or even prevent relapses in AML and MDS patients.36

More recently, there has been a growing interest in evaluating HMA as partners to novel promising agents such as the BCL2 inhibitor venetoclax, ICPs, FLT3 inhibitors, as well as isocitrate dehydrogenase (IDH) inhibitors and studies are ongoing (Table 1).

Table 1 Some of the Ongoing Trials Evaluating Various Targets for Post-Allogeneic Stem Cell Transplantation Strategies

The class I/II HDACi have presented as potential promising agents in AML/MDS owing to large induction effects on cell-cycle arrest and differentiation, as well as pro-apoptotic effects on myeloid cells through epigenetic modifications of histones.37 HDACi have also exhibited some antileukemic and immunomodulatory roles through the control of cytokine secretion. This is further evidenced by the panobinostat activity, a potent oral inhibitor of class 1, 2, and 4 deacetylases, in the PANOBEST trial.38 This study enrolled 42 patients with high-risk AML or MDS who had received ASCT and panobinostat was started at a median of 98 days (60150) post-ASCT. Two-thirds of these patients were transplanted in active disease. While only 22 (54%) of the 42 patients completed 1 year of therapy because of adverse events, the cumulative incidence at relapse remained 21% at 2 years, resulting in 2-year OS and DFS rates of 88% and 74%. More importantly, panobinostat was found to inhibit the suppressive function of T-regs when used at low doses and enhance their function at higher doses,39 thereby playing a possible role in reducing GVHD. As these results are intriguing, a randomized multicenter phase III trial is currently comparing panobinostat 20 mg orally three times weekly every second week to the standard of care as maintenance post-ASCT. Vorinostat, another HDACi, is also being combined with low-dose azacytidine for post-ASCT in a currently ongoing phase I dose-escalation clinical trial.

Treatment of FLT3-ITD mutated AML remains challenging due to significant relapse rates and short remissions with available therapies despite the common historical use of ASCT in first CR.40 Nevertheless, FLT3-mutated AML is a heterogeneous disease that entails diversity in the type of FLT3 mutations and their insertion site, the FLT3-ITD allelic burden, and the presence of concurrent mutations; observations that further complicated the decision to proceed to ASCT in the first CR when feasible.4143 This controversy is evidenced by the European LeukemiaNet guidelines suggesting, with some controversy, that ASCT should not be offered to patients with low-mutant allelic ratio.4446 EBMT guidelines allowed ASCT in this setting and recommended it for all patients with FLT3-mutated AML (Bazarbachi et al, 2020).47

As such, the use of multi-kinase inhibitors of various generations has led to improved outcomes and achievement of deeper responses in FLT3-mutated AML. These TKIs, together with the incorporation of MRD assessment, have enabled the installation of post-transplant therapeutic strategies,48 as the 1-year OS of patients who relapse post-ASCT drops to less than 20%.11 (Bazarbachi et al, 2020).12

The enthusiasm of using FLT3 TKIs stems not only from their direct cytotoxic properties but also involve an immunomodulatory effect synergizing with allografted T-cells. Several murine models have shown that sorafenib enhances the production of interleukin-15 (IL-15) production by leukemic cells, thereby promoting GVL effect.16 The same experiment showed that sorafenib reduced the activating transcription factor (ATF4) expression in leukemic cells, a negative regulator of IRF-7 interferon regulatory factor-7 (IRF-7) activation, which further enhances IL-15 transcription when activated. The exact mechanisms of FLT3 TKIs immunogenicity remain to be elucidated.

One of the earliest and most promising post-transplant maintenance approaches has been the administration of FLT3 inhibitors, limited to date to FLT3-ITD mutated AML patients. Despite multiple retrospective and prospective randomized trials evaluating the efficacy and safety of the use of FLT3 inhibitors as post-transplant maintenance, there is still a debate on the best agent to be used (off-label use of sorafenib versus potent second-generation FLT3 inhibitors), dosing and time of initiation. A consensus by the EBMT Acute Leukemia Working Party recommended the use of sorafenib 400 mg twice daily in the post-transplant setting in the absence of active GVHD based on available data (Bazarbachi et al, 2020).47 Previous retrospective studies have demonstrated a lower risk of disease relapse following ASCT in patients with FLT3 ITD mutated AML who received post-transplant sorafenib maintenance (Antar, et al, 2014).4953

In a phase I study involving 22 patients with FLT3-ITD AML receiving sorafenib maintenance post-ASCT, PFS at 1 year was 85% and OS was 95%.54 Encouraging results were subsequently reported in other small trials of sorafenib maintenance compared to historical controls, showing markedly lower relapse rates, improved RFS and relatively tolerable toxicities, while not significantly affecting the rates of GVHD.5153,5557 This is further supported by two registry studies from the European Society for Blood and Marrow Transplantation (EBMT) showing that post-transplant maintenance with sorafenib improved OS and leukemia-free survival (LFS) of allografted patients with FLT3-ITD positive AML (Bazarbachi et al, 2019)58 and that sorafenib combined with DLI clearly improved OS and LFS of relapsed FLT3-ITD positive AML patients following ASCT. (Bazarbachi et al, 2019)59

In a prospective phase II controlled randomized trial (SORMAIN) of 83 patients with FLT3-ITD mutated AML, the administration of sorafenib for up to 24 months resulted in superior outcomes for patients in CR and no grade 2 GVHD compared to placebo. After a long median follow-up of 42 months, the 2-year RFS was 85% in the sorafenib group compared with 53% in the placebo group (HR=0.39, p=0.01), in addition to an OS benefit for the sorafenib group (HR=0.447; p=0.03).60 Further follow-up showed that many patients will experience disease relapse when sorafenib is stopped at 24 months, suggesting a longer exposure to sorafenib might be needed to prevent late relapses. While SORMAIN trial constitutes the first placebo-controlled evidence that post-HSCT maintenance therapy could reduce the risk of relapse and death, this study enrolled patients who underwent transplantation in the first hematological CR, as well as those in the second or subsequent CR. Finally, the Chinese open-label, large randomized phase III trial assigned patients to receive sorafenib maintenance (n=100) or control (n=102) post-ASCT (Xuan et al 2020).61 At a median follow-up of 21.3 months, the 1-year cumulative incidence of relapse was 7.0% (95% CI 3.113.1) in the sorafenib group and 24.5% (16.633.2) in the control group (hazard ratio 0.25, 95% CI 0.110.57; p=0.0010), with no treatment-related deaths and acceptable GVHD rates. Based on these available data, sorafenib is recommended by many authorities as a maintenance strategy to reduce post-ASCT relapses for FLT3-ITD-mutated AML (Bazarbachi et al, 2020).47

More recent data from the RATIFY trial that led to the US Food and Drug Administration (FDA) approval of midostaurin in 2017, proposed that the outcomes of patients who received this agent prior to ASCT were particularly encouraging.62 In a phase II trial of midostaurin received as post-consolidation or post-ASCT maintenance, the 1-year relapse rate was encouragingly low at 9.2%.63 In this German-Austrian AML Study Group 1610, most patients discontinued midostaurin earlier than planned because of toxicities. This remains in line with prior reports on the drugs complex pharmacokinetic profile and drugdrug interactions that warrant close observation and dose adjustments to reduce toxicity.64,65

RADIUS is another phase II randomized study that accrued 60 patients with FLT3-ITD AML with stable engraftment post-ASCT to receive or not midostaurin for twelve 4-week cycles.66 Unsurprisingly, the median RFS was not reached for either arm as the trial was not powered to detect any statistical difference (p=0.34) between subgroups.

The prospective cooperative group international phase III randomized trial (BMT-CTN 1506; NCT02997202) is seeking to confirm the impact of post-transplant gilteritinib maintenance therapy versus placebo in patients with FLT3-mutated AML and has completed accrual at 346 patients. Gilteritinib is an effective and tolerable FLT3 inhibitor, with potent activity against both FLT3-ITD and FLT3-TKD mutations, particularly the kinase domain mutations at residue D835 and the gatekeeper mutation at residue F691.67 Gilteritinib was recently approved for use in the relapsed/refractory setting68 and was chosen for evaluation as post-ASCT maintenance owing to its safety profile and potent inhibition of FLT3 in vivo. Unfortunately, the use of placebo as control arm in this trial will not allow to answer the important question of whether Gilteritinib offers an additional benefit over sorafenib in that setting.

Quizartinib (AC220), a highly potent selective FLT3-ITD inhibitor was also studied in one small phase I trial where only 1 of 13 patients relapsed under therapy at the last follow-up.69 Furthermore, toxicities were manageable and GVHD rate was not increased. However, increasing reports about resistance through point-mutant forms have been emerging, hence limiting single-agent use.70

Crenolanib, like gilteritinib, is another potent oral type 1 FLT3 TKI with extended activity against FLT3-ITD and resistance-conferring FLT3-D835 TKD mutants.71 It is also under evaluation as a post-ASCT maintenance in a phase II trial (NCT02400255), in a cohort of patients transplanted in CR and in another group allografted with the residual disease with 10% bone marrow blasts. Crenolanib is started between days 45 to 90 after ASCT and for up to 2 years. It is important to note that phase II/III trials of post-ASCT maintenance involving the novel FLT3 TKIs do not use a first-generation inhibitor control, making it difficult to establish their superior efficacy in this setting.

Some unanswered questions remain regarding the use of FLT3 TKIs as maintenance post-ASCT. FLT3-ITD mutations, unlike BCR-ABL1 fusions,72 are not founding mutations but rather an important final step and one of many mutations found in leukemogenesis.73,74 These include WT1, IDH1, DNMT3A, as well as NUP98/NSD1 fusions, which are currently known to affect outcomes and response to therapy. Furthermore, FLT3 measuring assays are not cross-validated within trials along with considerable variability in the FLT3-ITD cut-off used (0.5 in the ELN recommendations, 0.7 in the RATIFY study) for treatment, as well as the dynamic changes that happen to this ratio over time. Until standardization of definitions, the indication of ASCT remains itself controversial in patients with low (<0.5) allelic ratio FLT3-ITD who have a concomitant NPM1 mutation and achieve MRD negative status on therapy (Bazarbachi et al, 2020).47

Ivosidenib and enasidenib have been recently approved for the treatment of IDH1 and IDH2-mutated AML, respectively.75,76 Owing to the natural history of this subtype of AML and the relative safety of these agents, they could present as a promising option for maintenance therapy post-ASCT. Some trials (NCT03515512, NCT03564821) are currently evaluating the significance of these mutations and their role in post-ASCT relapses, as well as the safety of the corresponding targeted agents in this setting.

Venetoclax is a BCL2 inhibitor that competitively binds to the BH3 domain of BCL2, an anti-apoptotic protein, releases BH3-only proteins and induces apoptosis of hematologic malignant cells.77 Venetoclax has been evaluated and is currently approved in combination with low-dose cytarabine and azacitidine or decitabine.78,79 These studies have included only a few patients who relapsed after ASCT and still achieved CR with the combination. Two prospective trials investigating the efficacy of venetoclax in combination with azacitidine at improving RFS are currently enrolling AML patients for maintenance or preemptive therapy post-ASCT.

Anomalous hedgehog (Hh) pathway signaling is involved in the survival and proliferation of leukemia stem cells,80 especially those resistant to chemotherapy.81 Glasdegib, an oral small Hh inhibitor, has been recently FDA approved in combination with low-dose cytarabine for the treatment of AML patients not eligible for intensive therapy, after showing OS benefit.82 Based on these findings, glasdegib is currently being evaluated in a phase II study for post-ASCT maintenance for AML patients at high-risk of relapse (NCT01841333).

AML and MDS with abnormal 17p or mutated p53 are known to portend dismal outcomes with the highest risk of relapse even in the post-ASCT phase.83 APR-246 is an agent that targets p53 mutation in an attempt to restore its function and showed up to 80% CR rate in an early trial of patients with myeloid malignancies.84 Based on this concept, a phase II trial studying the combination of azacytidine and APR-246 is currently enrolling allografted patients with MDS and AML and mutated p53 (NCT03931291) with a primary endpoint being 1-year RFS.

The use of antibody-drug conjugates (ADC) could achieve target specificity through inhibition of certain surface markers, such as CD33, expressed on the majority of myeloblasts. Gemtuzumab ozogamicin (GO) is a MoAb against CD33 conjugated to the toxin calicheamicin. In a small study of 10 relatively young patients allografted for high-risk AML, GO was administered with azacitidine as maintenance post-ASCT.85 After a median number of 1.5 cycles only complicated by reversible hematological toxicities, 40% of patients relapsed.

Another newer generation anti-CD33 ADC Vadastuximab talirine (SGN33a) conjugated to a pyrrolobenzodiazepine dimer was studied as maintenance in the post-ASCT setting (NCT02326584), but the phase I/II trial was terminated early because of neutropenia and thrombocytopenia.

Maintenance therapy with immune checkpoint inhibitors, such as nivolumab, is being investigated in clinical trials for patients with high-risk AML in remission post-consolidation, who are not candidates for ASCT.86 For instance, using this selective immune modulation for post-ASCT maintenance may provide similar benefits and merits investigation owing to their inherent activity in AML. Nonetheless, issues related to acute GVHD are likely to emerge, as seen with previous studies of lenalidomide in this setting,87 thereby limiting the wide adoption of these agents.8890

Other agents on the outlook in this setting include anti-chemokine (C-X-C motif) receptor 4 (CXCR4) as well as CAR T-cell therapy.

AML has increasingly presented itself as a poster child for personalized treatment approaches. ASCT by itself should not be regarded as an ultimate definitive therapy for all patients and with established poor outcomes for post-ASCT relapses, preventing one remains more beneficial than treating it. Nonetheless, we still have no simple algorithm or strategy to address post-ASCT relapses or maintenance approaches. As delineated above, most available information is derived from phase II trials of HMAs and FTL3-ITD TKIs and few randomized data. Recent development of targeted agents made their use in the post-transplant setting more exciting taking into consideration the potential risks on GVHD and immune reconstitution post-ASCT. Furthermore, better MRD assessments facilitated the optimal selection of high-risk candidates who would benefit from such strategies.

Any treatment decision should therefore involve the patients performance status, the pre-transplant disease course, the presence of actionable mutations, and the use of concurrent immunosuppressive medications as well as GVHD. Prognostication of high-risk AML patients has been recently refined, especially with the introduction of various MRD assays. These include MFC5,91 and NGS-MRD monitoring, both shown to be predictive for post-transplant relapse and survival.92,93

In our clinical practice, we utilize patient and disease characteristics coupled with pre- and post-transplant MRD assays as metrics to counsel patients about their risk of relapse. Awaiting further validation, we believe these are useful parameters, especially when conjugated to risk-stratified maintenance approaches. Nonetheless, we recommend the use of off-label FLT3-TKIs such as sorafenib because of our favorable experience and the accumulating data with this regard, which led to the EBMT recommendations (Bazarbachi et al, 2020).47 HMAs still represent a cornerstone maneuver to upregulate neoantigens and modulate immune responses post-ASCT when used alone or in various upcoming combinations (HMA+ DLI or venetoclax, etc.). One would, however, ask if pre-transplant therapy matters in this setting and whether responding favorably or not to azacitidine as initial therapy could affect the outcomes of post-ASCT maintenance. Novel agents such as ADCs and BCL2-inhibitors may provide a favorable approach despite little knowledge about the effect of these molecules on the graft and their potential toxicities. Immune stimulation with agents such as ICPs currently remains investigational awaiting well-designed clinical trials. Additionally, we must continue to explore the genetic profiling of AML and its ramifications.

Disease relapse remains a paramount endpoint to treating physicians and patients, far beyond the use of survival endpoints alone based on small single-center trials. With the recent surge of therapeutic opportunities, the priority should be to tailor randomized trials with refined conditioning regimens to post-transplant strategies while routinely incorporating MRD and genomic assays. This will require a solid partnership between the transplant community, academia and the pharmaceutical institutions for innovative and well-integrated approaches. A model trial in this setting also needs to assess the activity of a certain approach and its effect on GVHD. There is a steadily increasing number of novel agents, mostly of oral bioavailability, which could be preferred for maintenance therapy owing to their activity, dosing schedules, as well as minimal hematological toxicities. Other areas of interest include the use of MoAbs, ICP inhibitors and possibly products of cellular engineering (vaccines, modified chimeric antigen receptor T-cells, etc.). As a reflection of toxicities, we strongly support the integration of quality-of-life (QoL) metrics and patient-reported outcomes as informative endpoints in the design of these prospective randomized trials.

The authors report no conflicts of interest in this work.

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