58% relapse free survival at 1 year post-transplant79% overall survival at 1 year post-transplant

BOSTON, July 21, 2021 (GLOBE NEWSWIRE) -- Aprea Therapeutics, Inc. (Nasdaq: APRE), a biopharmaceutical company focused on developing and commercializing novel cancer therapeutics that reactivate mutant tumor suppressor protein, p53, today announced positive results from its Phase 2 trial evaluating eprenetapopt with azacitidine for post-transplant maintenance therapy in patients with TP53 mutant MDS and AML.

In 33 patients enrolled in the trial, the relapse free survival (RFS) at 1 year post-transplant was 58% and the median RFS was 12.1 months. The overall survival (OS) at 1 year post-transplant was 79%, with a median OS of 19.3 months. Prior clinical trials evaluating post-transplant outcomes in TP53 mutant MDS and AML patients have reported a 1-year post-transplant RFS of ~30% and a median OS of ~5-8 months. In addition, the post- transplant regimen of eprenetapopt and azacitidine was well tolerated among patients in the clinical trial. The Company plans to discuss the data from this Phase 2 clinical trial with the U.S. Food and Drug Agency (FDA) in the second half of 2021 and expects to present data at a future scientific or medical conference.

The post-transplant RFS and OS data with eprenetapopt and azacitidine maintenance therapy in these very difficult-to-treat TP53 mutant MDS and AML patients are incredibly exciting, said trial principal investigator Asmita Mishra, M.D., of the H. Lee Moffitt Cancer Center and Research Institute. Although transplant is currently the only potentially curative treatment for patients with TP53 mutant MDS and AML, the risk of relapse with current standard of care remains unacceptably high and the median OS post-transplant is very limited at 8 months or less. Post-transplant maintenance therapy with eprenetapopt and azacitidine could, if approved, represent a new treatment paradigm that meaningfully improves outcomes for these patients with limited treatment options.

About Aprea Therapeutics, Inc.

Aprea Therapeutics, Inc. is a biopharmaceutical company headquartered in Boston, Massachusetts with research facilities in Stockholm, Sweden, focused on developing and commercializing novel cancer therapeutics that reactivate mutant tumor suppressor protein, p53. The Companys lead product candidate is eprenetapopt (APR-246), a small molecule in clinical development for hematologic malignancies and solid tumors. Eprenetapopt has received Breakthrough Therapy, Orphan Drug and Fast Track designations from the FDA for myelodysplastic syndromes (MDS), Orphan Drug and Fast Track designations from the FDA for acute myeloid leukemia (AML), and Orphan Drug designation from the European Commission for MDS and AML. APR-548, a next generation small molecule reactivator of mutant p53, is being developed for oral administration. For more information, please visit the company website at http://www.aprea.com.

The Company may use, and intends to use, its investor relations website at https://ir.aprea.com/ as a means of disclosing material nonpublic information and for complying with its disclosure obligations under Regulation FD.

About p53, eprenetapopt and APR-548

The p53 tumor suppressor gene is the most frequently mutated gene in human cancer, occurring in approximately 50% of all human tumors. These mutations are often associated with resistance to anti-cancer drugs and poor overall survival, representing a major unmet medical need in the treatment of cancer.

Eprenetapopt (APR-246) is a small molecule that has demonstrated reactivation of mutant and inactivated p53 protein by restoring wild-type p53 conformation and function thereby inducing programmed cell death in human cancer cells. Pre-clinical anti-tumor activity has been observed with eprenetapopt in a wide variety of solid and hematological cancers, including MDS, AML, and ovarian cancer, among others. Additionally, strong synergy has been seen with both traditional anti-cancer agents, such as chemotherapy, as well as newer mechanism-based anti-cancer drugs and immuno-oncology checkpoint inhibitors. In addition to pre-clinical testing, a Phase 1/2 clinical program with eprenetapopt has been completed, demonstrating a favorable safety profile and both biological and confirmed clinical responses in hematological malignancies and solid tumors with mutations in the TP53 gene.

A pivotal Phase 3 clinical trial of eprenetapopt and azacitidine for frontline treatment of TP53 mutant MDS has been completed and failed to meet the primary statistical endpoint of complete remission. A Phase 1/2 clinical trial of eprenetapopt with venetoclax and azacitidine for the frontline treatment of TP53 mutant AML met the primary efficacy endpoint of complete remission. Additional clinical trials in hematologic malignancies and solid tumors are ongoing. Eprenetapopt has received Breakthrough Therapy, Orphan Drug and Fast Track designations from the FDA for MDS, Orphan Drug and Fast Track designations from the FDA for AML, and Orphan Drug designation from the European Medicines Agency for MDS and AML.

APR-548 is a next-generation small molecule p53 reactivator. APR-548 has demonstrated high oral bioavailability, enhanced potency relative to eprenetapopt in TP53 mutant cancer cell lines and has demonstrated in vivo tumor growth inhibition following oral dosing of tumor-bearing mice.

About MDS

Myelodysplastic syndromes (MDS) represent a spectrum of hematopoietic stem cell malignancies in which bone marrow fails to produce sufficient numbers of healthy blood cells. Approximately 30-40% of MDS patients progress to acute myeloid leukemia (AML) and mutation of the p53 tumor suppressor protein is thought to contribute to disease progression. Mutations in p53 are found in up to 20% of MDS and AML patients and are associated with poor overall prognosis. There are no currently approved therapies specifically for TP53 mutant MDS or AML patients.

About AML

AML is the most common form of adult leukemia, with the highest incidence in patients aged 60 years and older. AML is characterized by proliferation of abnormal immature white blood cells that impairs production of normal blood cells. AML can develop de novo or may arise secondary to progression of other hematologic disorders or from chemotherapy or radiation treatment for a different, prior malignancy; secondary AML carries a worse prognosis than de novo AML. Mutations in TP53, which are associated with poor overall prognosis, occur in approximately 20% of patients with newly diagnosed AML, more than 30% of patients with therapy-related AML and approximately 70-80% of patients with complex karyotype.

Forward-Looking Statement

Certain information contained in this press release includes forward-looking statements, within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, related to our study analyses, clinical trials, regulatory submissions, and projected cash position. We may, in some cases use terms such as future, predicts, believes, potential, continue, anticipates, estimates, expects, plans, intends, targeting, confidence, may, could, might, likely, will, should or other words that convey uncertainty of the future events or outcomes to identify these forward-looking statements. Our forward-looking statements are based on current beliefs and expectations of our management team that involve risks, potential changes in circumstances, assumptions, and uncertainties. Any or all of the forward-looking statements may turn out to be wrong or be affected by inaccurate assumptions we might make or by known or unknown risks and uncertainties. These forward-looking statements are subject to risks and uncertainties including risks related to the success and timing of our clinical trials or other studies, risks associated with the coronavirus pandemic and the other risks set forth in our filings with the U.S. Securities and Exchange Commission. For all these reasons, actual results and developments could be materially different from those expressed in or implied by our forward-looking statements. You are cautioned not to place undue reliance on these forward-looking statements, which are made only as of the date of this press release. We undertake no obligation to publicly update such forward-looking statements to reflect subsequent events or circumstances.

Source: Aprea Therapeutics, Inc.

Corporate Contacts:

Scott M. Coiante Sr. Vice President and Chief Financial Officer 617-463-9385

Gregory A. Korbel Sr. Vice President and Chief Business Officer 617-463-9385

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Aprea Therapeutics Announces Positive Results from Phase 2 Trial of Eprenetapopt + Azacitidine ... - The Bakersfield Californian

Bone Marrow Stem Cells Comments Off on Aprea Therapeutics Announces Positive Results from Phase 2 Trial of Eprenetapopt + Azacitidine … – The Bakersfield Californian | July 22nd, 2021

SAN DIEGO--(BUSINESS WIRE)--Stemson Therapeutics announced today the closing of a DCVC Bio-led $15 million Series A financing to advance development of Stemsons proprietary therapeutic solution to cure hair loss. Genoa Ventures, AbbVie Ventures and other investors join in supporting Stemsons efforts to restore human hair growth with a novel cell regeneration technology using the patients own cells to generate new hair follicles.

In addition, Kiersten Stead, Ph.D., Co-Managing Partner at DCVC Bio and Jenny Rooke, Ph.D., Managing Director at Genoa Ventures will join Stemsons Executive Chairman Matt Posard and Chief Executive Officer and co-founder Geoff Hamilton on the board of directors. Dr. Stead invests in early-stage companies that build novel deep tech businesses in the life sciences. Stead received a Ph.D. in Molecular Biology & Genetics and an MBA in finance from the University of Alberta. Dr. Rooke is founder and Managing Director at Genoa Ventures where she specializes in early-stage companies innovating at the convergence of technology and biology. Rooke received a Ph.D. in Genetics from Yale University and a degree in physics from the Georgia Institute of Technology.

We are excited and honored to welcome DCVC Bio and a fantastic syndicate of investors to the Stemson team. The Series A funding will help us optimize our solution for human skin structure and environment so we can go into our first human clinical trial with high confidence for a positive outcome. We have the technical and biological building blocks to successfully address hair loss that overcomes failures of past therapies, said Hamilton. The addition of key venture capital investors DCVC Bio, Genoa Ventures and AbbVie Ventures broadens and strengthens our investor base. DCVC Bio and Genoa Ventures are successful early-stage development investors, and I am pleased to welcome Dr. Stead and Dr. Rooke, our newest board members, to the team. In addition, the AbbVie Venture investment comes on the heels of an initial seed investment from Allergan Aesthetics in 2020, and the continued industry interest in our technology is encouraging.

Globally, hundreds of millions of men and women suffer from various forms of hair loss. Though there are many possible causes of hair loss, including chemotherapy, autoimmune disease, scarring, and genetics, all can result in a loss of self-esteem and cause depression, anxiety and other mental health disruption for those affected. The hair restoration market is expected to exceed $13.6 billion by 2028, and no solution today is capable of generating an unlimited new supply of healthy follicles for patients in need.

Almost 30 years have passed since the last FDA-approved hair loss treatment, yet millions still suffer the physical and mental impact of losing their hair each year, stated Dr. Stead. Stemsons novel stem cell engineering platform has the potential to cure hair loss once and for all, treating not only the physical symptoms of this complex problem, but the mental burden as well.

"The team at Genoa is impressed with Stemsons vision to blend biology and technology and apply it beyond traditional biotech," added Dr. Rooke. "By combining exciting advancements in iPSCs with novel technologies in materials and data sciences, Stemson exemplifies the kind of chimeric teams Genoa seeks to support on their journey to become a category-defining company."

The Series A financing brings the total funding raised to date to $22.5 million and allows Stemson to further the next stage of research and development of its cell engineering platform, where is it being combined with bioengineered material and robotic delivery as a novel solution for natural hair replacement. Currently, Stemsons research and development efforts are focused on developing an optimized solution for human skin structure environment in larger animal models. Stemsons Induced Pluripotent Stem Cell (iPSC) based technology is capable of producing the cell types required to initiate hair follicle growth and have been successfully tested in small animal models.

About Cell Regeneration Technology

Human Induced Pluripotent Stem Cells (iPSC) have the unique capability to replicate indefinitely and give rise to all cell types of the human body, including the cell types required for repair. iPSC-based technology is capable of producing the cell types required to initiate hair follicle growth. As a new therapeutic platform, iPSCs represent an emerging area of regenerative cell therapy. Stemson is one of a growing number of companies at the forefront in developing iPSC-based treatments.

About DCVC Bio

For over twenty years, DCVC and its principals have backed brilliant entrepreneurs applying Deep Tech, from the earliest stage and beyond, to pragmatically and cost-effectively tackle previously unsolvable problems in nearly every industry. DCVC Bio specializes in supporting life sciences platform companies at the intersections of engineering and therapeutics, industrial biotechnology and agriculture. For more information, please visit https://www.dcvc.com/companies.html#dcvc-bio

About Genoa Ventures

Genoa Ventures invests in early-stage companies working at the convergence of biology & technology to accelerate the pace of innovation, transform industries, and solve some of the most fundamental challenges to life. Genoa, identifies opportunities early and focuses its investments and expertise to empower the next great category-defining companies. The Genoa team has a unique chimeric blend of experience from scientific research and discovery to executive management in the life sciences and technologies sectors. The team applies this diverse experience to provide expert guidance to its companies and stellar returns to its investors.

About AbbVie Ventures

AbbVie Ventures is the corporate venture capital group of AbbVie. We are a strategic investor, investing exclusively in novel, potentially transformational science aligned with AbbVie's core R&D interests. We measure success primarily by the extent to which our investments foster innovation with potential to transform the lives of patients that AbbVie serves. AbbVie Ventures enables its portfolio companies with both funding as well as access to AbbVie's internal network of experts across all phases of drug development, from drug discovery through commercialization. For more information, please visit http://www.abbvie.com/ventures

About Stemson Therapeutics

Stemson Therapeutics is a pre-clinical stage cell therapy company founded in 2018 with a mission to cure hair loss by leveraging the regenerative power of Induced Pluripotent Stem Cells. Based on the breakthrough innovation by Stemson Therapeutics co-founder, Dr. Alexey Terskikh, Stemson uses iPSC to regenerate the critical cells required to grow hair and which are damaged or depleted in patients suffering from hair loss. The iPSC-derived cells are used to grow de novo hair follicles, offering a new supply of hair to treat people suffering from various forms of Alopecia. Today, there are no available treatments capable of growing new hair follicles. Stemsons world class team of scientists, advisors and collaborators are passionate about delivering a scientifically based, clinically tested cure for hair loss to the millions of hair loss sufferers who seek help for their hair loss condition. Stemson Therapeutics is headquartered in San Diego, CA. For more information, please visit http://www.stemson.com.

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Stemson Therapeutics Secures $15M Series A Funding to Cure Hair Loss - Business Wire

Skin Stem Cells Comments Off on Stemson Therapeutics Secures $15M Series A Funding to Cure Hair Loss – Business Wire | July 22nd, 2021

Dr. Bill Cimikoski, Medical Director of Utah Stem Cellsjoined Surae on The Daily Dish to discuss the BodyTite and Facetite procedures. He tells Surae that these procedures are excellent for getting rid of unwanted fat, while at the same time shrink wrapping the skin so that any loose skin is simultaneously tightened at the same time.

For some individuals, there may only be minimal (or none at all) fat to extract and it might be only necessary to tighten the skin. Depending on the area Utah Stem Cells are treating, they often see that in some individuals, there isnt really any fat to speak of and their patients are just looking for skin tightening and this is an excellent way to achieve that goal!

Unfortunately, on the other hand, some patients do have a large amount of fat in certain areas and then this device is also accompanied by liposuction. This is where they can suck the fat in addition to tightening the loose skin at the same time.This procedure is called Radio Frequency assisted Liposuction. At Utah Stem Cells they also offer High Definition Radio Frequency assisted liposuction to sculpt abs.

They offer many different treatments for different areas of the body, including the following:

All procedures are in-office and with only small holes or needle punctures, which heal completely without scarring. There is no need for general anesthesia and all are completed with lidocaine fluid although they do offer nitrous oxide, ketamine, and other methods to keep people comfortable and less anxious.

As a special gift, anyone who calls in after viewing The Daily Dish today will be entitled to $200 off any procedure.

To find out more about how Dr. Bill Cimikoski and Utah Stem Cells can help you, visit their website or you can give them a call at Phone number: (801) 999-4860

This article contains sponsored content.

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Learn how to remove unwanted fat with procedures beyond liposuction - ABC 4

Skin Stem Cells Comments Off on Learn how to remove unwanted fat with procedures beyond liposuction – ABC 4 | July 22nd, 2021

Blood cancers are not like other cancers. Unlike a cancer that affects one region of the body, such as lung cancer afflicting the lungs, blood cancers affect the entirety of the body because blood flows throughout it. Blood cancers do not form a lump or tumor in a specific organ, potentially making blood cancers more difficult to detect.

Blood contains various components. Red blood cells, white blood cells, plasma, and platelets all combine to make blood. Blood cancers, which include lymphoma, leukemia and myeloma, affect different components of the blood and interfere in different ways with the normal function of blood in the body.

Lymphoma affects the lymphatic system, which includes white blood cells called lymphocytes. These cells help protect the body against infection, advises the health site OnHealth. Leukemia originates inside of the bone marrow. Production of an overabundance of white blood cells may impede the marrows ability to make sufficient red blood cells and plasma, states the Leukemia & Lymphoma Society. Myeloma affects plasma cells, a type of white blood cell that fights off infection. When they become cancerous, the affected white blood cells can manufacture an abnormal protein that may damage organs and bodily systems.

Individuals affected with lymphoma, leukemia or myeloma may not feel a tumor, but they can look out for other symptoms. These include:

Frequent infections;

Coughing or chest pain;

Fever or chills;

Ongoing weakness or fatigue;

Shortness of breath;

Night sweats; and/or

Itchy skin or rash.

Even though blood cancers differ from other cancers in the way they present and what parts of the body they affect, they often are initially treated in the same way. SurvivorNet, a cancer survivor resource, says chemotherapy and radiation can target these cancers. Stem cell transplant, also known as bone marrow transplant, is a much more common treatment for blood cancers. Stem cells may be extracted from the patient or received from a donor.

Those who suspect the presence of blood cancers should consult with a doctor who can order blood tests to form a diagnosis.

We are making critical coverage of the coronavirus available for free. Please consider subscribing so we can continue to bring you the latest news and information on this developing story.

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What sets blood cancers apart from other cancers? | Lifestyles | washtimesherald.com - Washington Times Herald

Skin Stem Cells Comments Off on What sets blood cancers apart from other cancers? | Lifestyles | washtimesherald.com – Washington Times Herald | July 22nd, 2021

Scientists say that base editing proved itself efficient in correcting a mutation in patient cells with the monogenic disease Alpha-1 antitrypsin deficiency (AATD). The disorder is a common inherited disease that affects the liver and the lungs.

Base editing is different from other forms of editing, including CRISPR, because the base editors do not induce a break in the DNA, which helps prevent double strand breaks, potential off-target editing, and unwanted mutations during cell repair.

Researchers at Boston Medical Center and Boston University used patient-derived liver cells (iHeps) that mimic the biology of liver hepatocytes, the main producers of alpha-1 antitrypsin protein in the body. The base editing technology corrected the Z mutation responsible for AATD and reduced the effects of the disease in the hepatocytes, demonstrating successful base editing in human cells.

The study (Adenine Base Editing Reduces Misfolded Protein Accumulation and Toxicity in Alpha-1 Antitrypsin Deficient Patient iPSC-Hepatocytes), published inMolecular Therapy,can help pave the way for future human trials, according to the research team.

AATD is most commonly caused by the Z mutation, a single base substitution that leads to AAT protein misfolding and associated liver and lung disease. In this study, we apply adenine base editors to correct the Z mutation in patient-induced pluripotent stem cells (iPSCs) and iPSC-derived hepatocytes (iHeps), wrote the investigators.

We demonstrate that correction of the Z mutation in patient iPSCs reduces aberrant AAT accumulation and increases its secretion. Adenine base editing (ABE) of differentiated iHeps decreases ER stress in edited cells as demonstrated by single-cell RNA sequencing. We find ABE to be highly efficient in iPSCs and do not identify off-target genomic mutations by whole genome sequencing.

These results reveal the feasibility and utility of base-editing to correct the Z mutation in AATD patient cells.

This study shows the successful application of base editing technology to correct the mutation responsible for AATD in liver cells derived from patients with this disease, said Andrew Wilson, MD, a pulmonologist at Boston Medical Center and an associate professor of medicine at the Boston University School of Medicine, who served as the studys corresponding author. I am hopeful that these results will create a pathway to use this technology to help patients with AATD and other monogenic diseases.

Base editors created by Beam Therapeutics were applied to induced pluripotent stem cells (iPS cells) from patients with AATD, and then again in hepatocytes that were derived from iPS cells. This was done to study the correction of the Z mutation of the gene responsible for AATD in human cells.

The Z mutation in the SERPINA1 gene is responsible for causing chronic, progressive lung and liver disease in AATD. In patients with AATD, the mutant AAT proteins misfold and form aggregates of protein that build up inside the hepatocytes and cause damage.

For this study, researchers started with mutant (ZZ) iPSCs created from a patient with AATD. After the base editing process was completed, the DNA from the edited cells was sequenced to determine if the SERPINA1 gene had been corrected. Clonal populations of cells with either one (MZ) or both copies (MM) of the corrected gene were expanded and then differentiated over the course of 25 days to generate hepatocytes.

After sequencing the entire genome of the edited cells, there was no evidence of inadvertent mutations in the genome from the base editors, and the misfolding and associated protein buildup was partially corrected in MZ cells and completely in MM normal cells.

The process was repeated using hepatocytes derived from the mutant iPSCs. Two base editors were used in different conditions to test the efficiency of this process. In the best conditions, about 50% of the mutant genes were successfully edited. The cells were then analyzed to see if they still appeared hepatic and if there were fewer signs of the disease in the edited cells, compared to mutant ZZ cells.

Findings showed the base editing did not alter the hepatic program, and the liver cells still expressed hepatic genes and proteins at normal levels. In addition, there was less accumulation of aggregated misfolded Z AAT protein, showing less evidence of disease in the edited cells.

While augmentation therapy has been shown to slow the progression of lung disease in AATD patients, there are currently no treatments available for AATD-associated liver disease. Emerging treatment strategies have focused on the correction of the Z mutation.

Base editing is being evaluated as a treatment modality for a variety of monogenic diseases, according to the scientists. Alpha-1 antitrypsin deficiency is a prime target for base editing, likely to be one of the earlier diseases in which base editors are tried in human studies. Additional disease targets include retinal disease, hereditary tyrosinemia, sickle cell anemia, progeria, cystic fibrosis, and others.

Findings of this study suggest that future research may explore the usefulness of base-editors in editing other quiescent cell populations. Additionally, it has recently been shown that base-editors can edit RNA in addition to DNA in immortalized cell lines and warrants further investigation.

By quiescent, we are referring to differentiated cells (in this case hepatocytes) that are not stem cells or cells that are actively dividing. Basically, [we are talking about] any differentiated cell type, Wilson toldGEN. This is relevant because many of the cell types in the body that you would want to target are already differentiated cells. It is in many cases easier to edit an actively dividing cell, which is why we mention this. There are many examples of a differentiated cell type in the body, such as cardiac cells, lung cells, skin cells, etc., that you might want to target.

One of the major things researchers worry about in the field of gene editing is the possibility of off-target effectsunintended consequences of applying the editing machinery.

The most likely off-target effect, in this case, would be editing of DNA somewhere in the genome other than what we intended to edit, continued Wilson. When we looked by whole genome sequencing, we didnt see evidence of this in iPS cells. However, in addition to editing DNA, it has been reported that base editors can also edit RNA. This could have unintended consequences even if the DNA sequence isnt changed.

We didnt look in this study to see if this occurred, which is why we mentioned itjust to be up front about possible unintended consequences/toxicities that could be present and that we didnt exclude. It isnt something specific to our study or gene of interest but generalizable to the entire field of base editing.

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Base Editing as Therapy for Common Inherited Lung and Liver Disease Shows Promise - Clinical OMICs News

IPS Cell Therapy Comments Off on Base Editing as Therapy for Common Inherited Lung and Liver Disease Shows Promise – Clinical OMICs News | July 22nd, 2021

Q: Im considering having my own stem cells injected into me to improve physical and mental problems that I am having post-COVID-19 infection. What do you think?

James D., Huntington, N.Y.

A: Theres been a lot of talk about using what are called autologous stem cells (your own) to fight off COVID-19 long-haul symptoms, as well as to treat everything from torn ligaments to Alzheimers disease. None is approved by the Food and Drug Administration. The only stem-cell-based products that are FDA-approved come from blood-forming stem cells (hematopoietic progenitor cells) derived from cord blood and theyre for treating disorders involving production of blood (the hematopoietic system). A list is at fda.gov; search for Approved Cellular and Gene Therapy Products.

In fact, stem cell/regenerative medicine treatment scams are so prevalent that this spring the FDA finally told manufacturers and marketers that they had to comply with regulations on human cell and tissue products. Unfortunately, a June report from Pew Trust found compliance by the companies and enforcement from the FDA to be anemic.

What the report did find was that more than 700 clinics in the U.S. offer unapproved stem-cell and regenerative medicine interventions for conditions such as Alzheimers, muscular dystrophy, autism, spinal cord injuries and, most recently, COVID-19. They also found post-injection infection happens frequently and is likely because of sloppily manufactured products and failure to properly screen for diseases such as HIV and hepatitis B and C.

If youre considering stem-cell treatment, the FDA urges you to ask the clinic for the following info before getting it even if the stem cells are your own:

Proof the FDA has reviewed and approved the treatment. Have your primary care doc confirm the information.

If the clinic is claiming it has an FDA-issued Investigational New Drug application number, ask for it and ask to review the FDA communication acknowledging the IND.

Stem-cell treatment has great potential, but when used for unapproved therapies outside a clinical trial, its risky (and expensive). To search for a trial, go to clinicaltrials.gov.

Q: My doctor says my high blood pressure puts me at increased risk for dementia. I think hes just trying to get me on one more med. Is there really a connection?

Lacie R., Sacramento, Calif.

A: Dementia means that you have cognition problems that cause trouble with memory, thought and everyday tasks. That could result from mini- or regular strokes, and we know that high blood pressure increases your stroke risk. In fact, one Harvard study found that high blood pressure increases a mans risk of stroke by 220 percent; another found that each 10 mmHg rise in systolic pressure (the top number) boosts your risk of ischemic stroke by 28 percent and of hemorrhagic stroke by 38 percent.

Even if your high blood pressure doesnt trigger a stroke, it can lead to impaired cognition and dementia. The 2018 SPRINT-MIND trial found that intensive control of high blood pressure (getting the top number below 120) lowered the risk of mild cognitive impairment by 19 percent compared with standard blood pressure control. Now, a new study in the journal Hypertension indicates that certain antihypertensive medications ACE inhibitors and ARBs (and angiotensin II receptor blockers) can cross the blood-brain barrier and lower dementia risk. Tracking almost 13,000 people for three years, the researchers found that folks taking those meds showed less memory loss than folks taking other sorts of antihypertensive medications.

You dont indicate how high your blood pressure is, but if it is only slightly elevated you may be able to bring it down through changing your diet, losing weight if you need to and exercising for 30 to 60 minutes five days a week. If it is above 125 (top number) or above 85 (bottom number), a combo of those self-care techniques and medication may be the safest choice. But either way, bringing your blood pressure to around 115/75 will protect your brain, as well as your heart, kidneys and eyes.

Contact Drs. Oz and Roizen at sharecare.com.

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Stemming the tide of stem-cell treatment scams - Houston Chronicle

Spinal Cord Stem Cells Comments Off on Stemming the tide of stem-cell treatment scams – Houston Chronicle | July 22nd, 2021

Researchers at the Chinese Academy of Sciences and University of Science and Technology of China have devised a novel bioprinting-based method of curing previously untreatable spinal cord injuries.

Using a custom bio-ink, the Chinese team have managed to 3D bioprint neural stem cell-loaded tissues capable of carrying instructions via impulses from the brain, much like those seen in living organisms. Once implanted into disabled rats, the scaffolds have shown the ability to restore movement in paralyzed limbs, and the scientists now believe their approach could find human applications in future.

There is no known effective cure for spinal cord injury, Zhijun Zhang, a nanobiomedical engineer at the Chinese Academy of Sciences told the Scientist. The 3D bioprinting strategy weve developed, may represent a general and versatile strategy for rapid and precise engineering of the central nervous system (CNS), and other neuronal tissues for regenerative medicine.

The SCI injury conundrum

A Spinal Cord Injury or SCI is a blanket term used to describe any damage caused to the bundle of cells and nerves that send signals to and from the brain along the human spinal cord. While the damage itself can be caused either by direct injury, or from bruising to the surrounding vertebrae, the result is often the same: a partial or complete loss of sensory and locomotor function below the affected area.

While theres no current known cure for SCI, a number of promising cell-based therapies are now being developed, with the regeneration of functional neurons seen as central to their future success. In effect, such approaches involve re-establishing links between neurons throughout the injured area in order to restore nerve functionality, but repairing damaged cells continues to be problematic.

Where neural stem cells have previously been implanted into SCI sites, theyve also shown poor viability and uncontrolled differentiation, leading to low therapeutic efficacy. More recent efforts have seen scientists bioprint cell-loaded scaffolds, capable of creating a suitable microenvironment in which neurons can flourish, yet this has raised further issues around printability and initiating cellular interaction.

To get around these problems, the Chinese researchers have now developed a novel bio-ink that gels together at body temperature to prevent neurons from differentiating into cells that dont produce electrical impulses, and can be 3D bioprinted into scaffolds that not only mimic the white matter appearance of the spine, but encourage cell-to-cell interactions.

A paralysis cure in-action

To begin with, Zhang and his team formulated their bio-ink from natural chitosan sugars, as well as a mixture of hyaluronic acids and matrigel, before combining them with rat neural stem cells. The scientists then used a BioScaffolder 3D bioprinter to deposit the resulting concoction into cell-laden scaffolds, which were later stored in culture plates for further testing.

Prior to their implantation, the teams different samples were incubated for three, five and seven days respectively, during which they proliferated and formed connections. Interestingly though, the researchers found that the higher the concentration of hyaluronic acid, the lower levels of interaction they observed, showing that their bio-ink can be tweaked to achieve desired tissue characteristics.

When injected into paraplegic lab rats, the scaffolds exhibited a cell viability of 95% while promoting neuron regeneration to the point that they enabled the rats to regain control over their hind legs. Over a 12-week observation period, the treated animals also showed a revived ability to move their hips, knees and ankles without support, and kick pressure sensors with markedly enhanced muscle strength.

As a result, the scientists have concluded that their approach offers a versatile and powerful platform for building precisely-controlled complex neural tissues with potential human applications, although they concede that more precise regulation of cell differentiation will be needed to achieve this, in addition to further testing on more clinically-relevant injury models.

Overall, this study clearly demonstrated for the first time the feasibility of the 3D bioprinted neural stem cell-laden scaffolds for SCI repair in-vivo, concluded the team in their paper, which, we expect, may move toward clinical applications in the neural tissue engineering, such as SCI and other regenerative medicine fields in the near future.

3D bioprinting in CNS treatments

Thanks to constant advances in flexible electronics and 3D bioprinting technologies, its now becoming increasingly possible to produce neural implants, with the potential to treat complex CNS injuries. Last year, a project started at TU Dresden led to the creation of 3D printed neural implants, capable of linking the human brain to computers as a means of treating neurological conditions such as paralysis.

In a similar study, engineering firm Renishaw has worked with pharmaceuticals expert Herantis Pharma to assess the performance of its 3D printed neuroinfuse drug delivery device. Designed to deliver intermittent infusions into the parenchyma, an organs functional tissue, the platform could be used as a future treatment for Parkinsons disease.

With regards to treating spinal injuries specifically, researchers at the University of California San Diego have also managed to repair spinal cord injuries in rats. By implanting 3D printed two-millimeter-wide grafts into test subjects, the team have been able to facilitate neural stem cell growth, restore nerve connections and ultimately help recover limb functionality in rodent test subjects.

The researchers findings are detailed in their paper titled 3D bioprinted neural tissue constructs for spinal cord injury repair. The study was co-authored by Xiaoyun Liu, Mingming Hao, Zhongjin Chen, Ting Zhang, Jie Huang, Jianwu Dai and Zhijun Zhang.

The nominations for the 2021 3D Printing Industry Awards are now open. Who do you think should make the shortlists for this years show? Have your say now.

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Featured image shows the researchers 3D bioprinted scaffolds after 7 and 21 days culturing. Images via the Biomaterials journal.

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Introducing the 3D bioprinted neural tissues with the potential to 'cure' human paralysis - 3D Printing Industry

Spinal Cord Stem Cells Comments Off on Introducing the 3D bioprinted neural tissues with the potential to ‘cure’ human paralysis – 3D Printing Industry | July 22nd, 2021

Wei Wu and Xiao-Ming Xu (Credit: IU School of Medicine)

Researchers at Indiana University School of Medicine (Indianapolis, USA) have announced the successful reprogramming of a glial cell type in the central nervous system into new neurons in order to promote recovery after spinal cord injuryrevealing an untapped potential to leverage the cell for regenerative medicine.

This is the first time that scientists have reported modifying a NG2 gliaa type of supporting cell in the central nervous systeminto functional neurons after spinal cord injury, saidWei Wu, research associate in neurological surgery at IU School of Medicine and co-first author of the paper, which was published in the Cell Stem Cell journal.

Wu andXiao-Ming Xu, the Mari Hulman George professor of Neuroscience Research at IU School of Medicine, worked on the study with a team of scientists from the University of Texas Southwestern Medical Center.

Spinal cord injuries affect hundreds of thousands of people in the United States, with thousands more diagnosed each year. Neurons in the spinal cord dont regenerate after injury, which typically causes a person to experience permanent physical and neurological ailments.

Unfortunately, effective treatments for significant recovery remain to be developed, Xu said. We hope that this new discovery will be translated to a clinically relevant repair strategy that benefits those who suffer from a spinal cord injury.

When the spinal cord is injured, glial cells, of which there are three typesastrocyte, ependymal and NG2respond to form glial scar tissue.

Wu added: Only NG2 glial cells were found to exhibit neurogenic potential in the spinal cord following injury in adult mice, but they failed to generate mature neurons. Interestingly, by elevating the critical transcription factor SOX2, the glia-to-neuron conversion is successfully achieved and accompanied with a reduced glial scar formation and increased functional recovery following spinal cord injury.

The researchers reprogrammed the NG2 cells from the mouse model using elevated levels of SOX2a transcription factor found inside the cell thats essential for neurogenesisto neurons. This conversion has two purposes, Xu said: to generate neurons to replace those lost due to a spinal cord injury and reduce the size of the glial scars in the lesion area of the damaged tissue.

This discovery, serves as an important target in the future for potential therapeutic treatments of spinal cord injury, adds Wu, who goes on to note that such a collaboration will be continued between the two laboratories to address neuronal remodelling and functional recovery after successful conversion of glial cells into functional neurons in future.

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IU School of Medicine researchers discover new potential for functional recovery after spinal cord injury - Spinal News International

Spinal Cord Stem Cells Comments Off on IU School of Medicine researchers discover new potential for functional recovery after spinal cord injury – Spinal News International | July 22nd, 2021

In the last few years, many researchers have discovered that mesenchymal stem cells (MSCs) hold the key to treating many serious diseases such as diabetes, Parkinsons disease, and multiple sclerosis. According to the study, Prevalence of Parkinsons disease (PD) across North America, published in July 2018 in the journal Nature, the number of people suffering from PD is expected to reach 930,000 in 2020 and 1,238,000 in 2030. Thus, high prevalence of such diseases is also expected to aid in growth of the mesenchymal stem cells market.

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While no one yet knows exactly how the cells work, scientists are excited about the potential benefits of using MSCs as treatment modalities. In particular, the discovery that stem cells can differentiate into other cell types has implications for the field of regenerative medicine. The potential of MSCs to provide treatments for age-related diseases is exciting. Thus, increasing geriatric population is also expected to aid in growth of the mesenchymal stem cells market.

While stem cells from adults hold the most promise for use in treating human illnesses, the discovery that adult stem cells can be directed to treat specific diseases has provided doctors with a new approach to the treatment of patients with life-threatening diseases, which in turn is expected to aid in growth of the mesenchymal stem cells market. Mesenchymal stem cells are found in the bone marrow in rich supply. Because the cells are continually being used to make blood, tissue, and organs, they are not only rich in blood, they are also rich in antigens. This allows adult stem cells to directly apply their healing properties to a host of diseases.

Adult MSCs have the potential to replace diseased or otherwise damaged adult stem cells in a variety of tissues throughout the body, including muscle, bones, and organs. Various researches have revealed exciting potential in using these cells to treat a range of debilitating diseases. For example, since MSCs can be directed to the myeloid tissues of the bone marrow, they can help to repair and regenerate tissue and organs that are injured or became infected. These studies are currently underway and have the potential to provide a major breakthrough in the treatment of many serious diseases, boosting growth of the mesenchymal stem cells market.

MSCs are also being tested to directly apply to a patients spinal cord to promote regrowth of bones and other skeletal tissues. This is done through the introduction of specialized cells into the spinal cord. Since the specialized cells that are made in the laboratory from MSCs can be directed to a number of myeloid tissues, they can provide a direct means of repairing and regenerating spinal cord injury, spinal stenosis, cervical spondylosis, spinal arthritis, etc. The long term effects of mesenchymal stem cells transplantation on the spinal cord are not yet known but the studies so far are very promising and the technology could very soon be available for clinical trials.

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Major Key Players Are: Pluristem Therapeutics, LonzaThermo, Fisher, ATCC, Bio-Techne, MilliporeSigma, Genlantis, Celprogen, Cell Applications, PromoCell GmbH, Cyagen Biosciences, Human Longevity Inc., Axol Bioscience, Cytori Therapeutics, Eutilex Co.Ltd., ID Pharma Co. Ltd., BrainStrom Cell Therapeutics, Cytori Therapeutics Inc., Neovii Biotech, Angel Biotechnology, California Stem Cell Inc., Stemcelltechnologies Inc., and Celgene Corporation Inc.

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Mesenchymal Stem Cells Market Witnesses Upward Trend with High Prevalence of Parkinson's Disease The Manomet Current - The Manomet Current

Spinal Cord Stem Cells Comments Off on Mesenchymal Stem Cells Market Witnesses Upward Trend with High Prevalence of Parkinson’s Disease The Manomet Current – The Manomet Current | July 22nd, 2021

The clinical evidence included high concentrations of C-X-C motif chemokine ligand 10 (CXCL10) and C-C motif chemokine ligand 2 (CCL2) in the cerebrospinal fluid (CSF) and serum samples.

This interim report supports the feasibility of generating HER2-specific CAR T cells for repeated dosing regimens and suggests that their repeated intra-CNS delivery might be well tolerated and activate a localized immune response in pediatric and young adult patients, Nicholas Alexander Vitanza, MD, an assistant professor at the Ben Towne Center for Childhood Cancer Research, and a staff member of the Cancer and Blood Disorders Center, Brain Tumor Program, Apheresis, at Seattle Childrens, and coauthors, wrote in the study publication.

Although the integration of CAR T-cell therapy has provided a novel therapeutic modality to manage multiple hematologic malignancies, the utility of CAR T cells is not fully understood for pediatric patients with CNS tumors.

HER2 offers a valid target for CAR T-cell therapy in CNS tumors because it is widely expressed on a significant proportion of biologically diverse CNS tumors such as ependymoma, glioblastoma, and medulloblastoma, as well as CNS cancer stem cells. Moreover, HER2 is not expressed on normal CNS tissue.

Monoclonal antibodies, such as trastuzumab (Herceptin), are beneficial for patients with some HER2-expressing cancers but have limited activity in CNS tumors that require a therapy that crosses the blood-brain barrier. CNS tumors also harbor less HER2 expression compared with malignancies like breast cancer.

As such, directly administering HER2-directed therapy to the tumor site could be a lucrative strategy for patients with CNS tumors.

Preclinical data demonstrated that spacer length was correlated with improved activity of HER2-specific CAR T cells. Based on this, the single-institution BrainChild-01 trial used a medium-length spacer HER2CAR to evaluate repeated locoregional delivery of HER2-specific CAR T cells for pediatric patients with recurrent or refractory CNS tumors.

Following CAR T-cell manufacturing, patients were treated in the outpatient setting for up to 6 courses. Course 1 consisted of 3 weeks of a 1 x 107 dose of CAR T cells (DL1), followed by clinical evaluation in week 4. Course 2 consisted of 1 week of DL1 treatment, 2 weeks of a 2.5 x 107 dose of CAR T cells (DL2), followed by clinical and radiographic evaluation in week 4. Courses 3 through 6 retained the same dosing schedule at the highest tolerated dosing levels, which included 2 additional tiers: 5 x 107 [DL3] and 10 x 107 [DL4].

The BrainChild-01 HER2CAR T-cell product was manufactured under a process designed to yield balanced numbers of CD4+ and CD8+ lentivirally transduced T cells exhibiting limited terminal differentiation with enrichment for the CAR+ population of cells mid-culture, Vitanza and coauthors wrote.

The initial 3 patients were required to be from 15 to 26 years old. This age group is more capable of self-reporting neurologic changes compared with a younger patient population, so they were specifically used for the initial evaluation.

The first eligible 3 patients underwent apheresis and had CAR T-cell products that were in-line with release criteria. As such, the patients were assigned to the appropriate treatment arms: repeated locoregional CNS infusion into the CNS tumor or tumor cavity (arm A; n = 1) vs repeated locoregional CNS infusion into the ventricular system (arm B; n = 2).

All patients had undergone at least 3 prior tumor-directed surgical procedures, at least 1 prior irradiation, and at least 1 prior chemotherapy regimen. Additionally, all patients had presumed pediatric biology of their tumors.

A 19-year-old female patient enrolled on arm A was diagnosed with WHO grade III localized anaplastic astrocytoma. She had 1.95 x 109 total nucleated cells manufactured and 1.87 x 109 EGFRt+ CAR T cells manufactured. She received 6 doses of treatment.

Both patients enrolled on arm B were males with WHO grade III metastatic ependymoma. The first, a 16-year-old, had 3.2 x 109 total nucleated cells manufactured, 2.97 x 109 EGFRt+ CAR T cells manufactured, and received 9 doses of treatment. The second patient, aged 26, had 2.06 x 109 total nucleated cells manufactured, 1.87 x 109 EGFRt+ CAR T cells manufactured, and received 9 doses of treatment. The latter patients product in arm B had initial failure of viability screening, but with 2 additional manufacturing attempts, enough CAR T cells were generated to complete a minimum of 2 treatment courses.

The study was designed to primarily assess feasibility, safety, and tolerability, with assessment of CAR T-cell distribution and disease response as secondary objectives.

Patients experienced post-treatment symptoms. One patient who underwent imaging experienced radiographic evidence of treatment-mediated localized CNS immune activation.

Additional results showed that the most common adverse effects (AEs) observed in all patients were headache, pain at metastatic sites of spinal cord disease, and transient worsening of a baseline neurologic deficit. Additionally, the 2 patients on arm B experienced fever within 24 hours following infusion. These AEs were deemed possibly, probably, or definitely related to CAR T-cell therapy.

Systemic C-reactive protein elevation was also noted in all patients and overlapped with the timing of headaches and/or pain.

Regarding CSF cytokines and radiographic imaging, CAR T cells were not detected in any patient at any time point following infusion in CSF via flow cytometry or in peripheral blood via quantitative polymerase chain reaction. NonCAR T cell populations of CD4+ and CD8+ T cells were detected in CSF after infusion.

Cytokines, including CXCL10, CCL2, granulocyte colonystimulating factor, granulocyte-macrophage colony-stimulating factor, IFN2, IL-10, IL12-p70, IL-15, IL1, IL-6, IL-7, and tumor necrosis factor, were detected in the CSF following infusion. One patient also had elevated VEGF.

Additional studies are planned to evaluate the relationship between target antigen density and clinical toxicity and response.

With these findings, the trial is planned to enroll the broader age cohort of patients aged 1 to 26 years. Notably, the trial will include patients with diffuse midline glioma.

Two additional studies are also planned. BrainChild-02 (NCT03638167) will deliver EGFR-specific CAR T cells to pediatric patients with recurrent or refractory EGFR-positive CNS tumors. BrainChild-03 (NCT04185038) will deliver B7-H3specific CAR T cells to pediatric patients with recurrent or refractory CNS tumors or diffuse intrinsic pontine glioma.

Gleaning the results of all 3 BrainChild studies, the investigators plan to use a multiplexed strategy to overcome tumor heterogeneity, which remains a challenge for drug development in this patient population, and antigen escape.

Ultimately, the experience of the initial three patients treated on BrainChild-01 suggests that repeated locoregional HER2-specific CAR T-cell dosing might be feasible and that correlative CSF markers might be valuable in assessing on-target CAR T-cell activity in the CNS, concluded Vitanza and coauthors.

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HER2-Specific CAR T Cells Induce Early Efficacy Without Dose-Limiting Toxicities in Pediatric CNS Tumors - OncLive

Spinal Cord Stem Cells Comments Off on HER2-Specific CAR T Cells Induce Early Efficacy Without Dose-Limiting Toxicities in Pediatric CNS Tumors – OncLive | July 22nd, 2021

The future is quite bright for multiple myeloma. We are really homing in on the best regimen for frontline therapy in transplant-eligible and -ineligible [patient populations], Martin said. We are also closer with our recommendations to figuring out how to treat early-relapsed multiple myeloma. We have a variety of novel drugs that are approved for use to treat [patients with] late relapse. That [setting] has been our unmet medical need, [historically].

Martin, a clinical professor of medicine in the Adult Leukemia and Bone Marrow Transplantation Program; associate director of the Myeloma Program; and co-leader of the Cancer Immunology and Immunotherapy Program at the Helen Diller Family Comprehensive Cancer Center of the University of California, San Francisco; added that there are several very exciting therapies under investigation in clinical trials, including BiTEs. [These therapies] are showing unprecedented responses in very refractory patients, [including] the triple-class exposed patients, which is amazing.

He spoke with OncLive during an Institutional Perspectives in Cancer webinar on multiple myeloma. He chaired the virtual meeting which covered updates in frontline, early-, and late-relapsed multiple myeloma, immunotherapy in multiple myeloma, and frontline and relapsed/refractory amyloidosis.

Martin discussed the latest news in frontline, early relapsed, and heavily pretreated multiple myeloma, including the growing promise of quadruplets, emerging targets beyond BCMA, and the potential emergence of quadruplets, venetoclax (Venclexta), and antiviral therapy in amyloidosis.

Martin: For frontline therapy in multiple myeloma, we break [our algorithm] up [according to] patients who are fit and [unfit. Patients who are fit] can likely go to stem cell transplant. A quadruplet is going to be where we are headed, and it is going to be [a quadruplet using] the 3 different classes of drugs: a monoclonal antibody, an immunomodulatory drug [IMiD], and a proteasome inhibitor [PI], together with a steroid. [The combination of] those 4 classes of drugs [were evaluated] in the GRIFFIN [NCT02874742] and Cassiopeia trials [NCT02541383]. The GRIFFIN trial looked at daratumumab [Darzalex], lenalidomide [Revlimid], bortezomib [Velcade], and dexamethasone, whereas the Cassiopeia trial looked at daratumumab, thalidomide [Thalomid], and dexamethasone. Both [trials] showed spectacular early responses for induction therapy to [the respective] quadruplets.

Another study looked at daratumumab [plus] carfilzomib [Kyprolis], lenalidomide, and dexamethasone [KRd]. That trial too showed unprecedented early responses as frontline therapy. More studies are looking at other CD38[-directed monoclonal antibodies], like isatuximab-irfc [Sarclisa], together with lenalidomide, as well as KRd.

These quadruplets are showing fast and deep responses after 4 cycles [of treatment]. For patients who are transplant eligible, [treatment with a quadruplet] prepares them for transplant quite well. They can go into transplant with a nice, deep response and, hopefully, [derive] a deeper response after remission.

The question exists of whether the quadruplets and other therapies may take away the need for autologous stem cell transplant. Right now, transplant is still part of frontline therapy and is especially useful in patients who have high-risk disease.

In the transplant-ineligible population, the MAIA trial [NCT02252172] looked at daratumumab plus lenalidomide and dexamethasone vs lenalidomide and dexamethasone. The triplet has shown a median progression-free survival [PFS] approaching 60 months; that is just amazing for frontline therapy. We will see if quadruplets are needed in the transplant-ineligible setting.

We have several trials testing quadruplet therapy in the transplant-eligible population. Both daratumumab and isatuximab are being combined with IMiDs, PIs, and dexamethasone in a randomized fashion [vs triplet therapy]. We will see what the winner is. It will be interesting as we move forward, but right now, if we start that triplet therapy, we expect a PFS of 60 months, which is just amazing.

When we think about early relapse, what becomes important is what patients were on when they became relapsed or refractory. If they were on an IMiD, most of the time it was lenalidomide as maintenance therapy. We would then consider that patient lenalidomide refractory. In that scenario, we would use a CD38[-directed monoclonal antibody] plus pomalidomide [Pomalyst] and dexamethasone or a CD38[-directed monoclonal antibody] plus a PI and dexamethasone.

The data with daratumumab plus pomalidomide and dexamethasone, as well as isatuximab plus pomalidomide and dexamethasone, are quite good. Truthfully, my favorite [approach] is that if the patient is on an IMiD, I give an antibody together with a PI. The IKEMA [NCT03275285] and CANDOR [NCT03158688] studies have shown deep and durable responses with a CD38[-directed monoclonal antibody] plus carfilzomib and dexamethasone in the early-relapsed setting.

The CANDOR study showed a PFS of about 28 months. We still need longer follow-up from the IKEMA study to see what the PFS is going to be, but it is certainly going to be at least 28 months. Specifically, [in the IKEMA] study we showed that 30% of patients had achieved minimal residual disease [MRD] negativity with the triplet combination in the early-relapsed setting. Its unprecedented to see these deep responses with evidence of MRD negativity.

If patients have not received a CD38[-directed monoclonal antibody] as part of frontline therapy, that is what the first component should be to add for first relapse. The other regimens, which weve used before and are good, include pomalidomide, bortezomib, and dexamethasone, or pomalidomide, carfilzomib, and dexamethasone. There are multiple other choices, but those are my favorites.

In early-to-mid relapse, we usually use a ping-pong approach where we go back and forth between the categories of agents. Eventually, after 2 or 3 lines of therapy, patients have been exposed to what I call the big 5, which are lenalidomide, bortezomib, carfilzomib, pomalidomide, and a CD38-directed antibody. This is a setting which had been our unmet medical need.

We now have 3 agents that are FDA approved for that group of patients. We have selinexor [Xpovio] plus dexamethasone, which was approved based on the STORM trial [NCT02336815]. That doublet can be used in the [originally indicated] twice-weekly [dose], or given once weekly, which is much better tolerated. Often, we combine [selinexor] with another agent, such as bortezomib, carfilzomib, pomalidomide, or, even, daratumumab, so it is a kind of pick-your-partner [agent] in that regard. There are toxicities associated with selinexor, and we must follow patients closely. We cant just give them the therapy and see them in 4 weeks. We must follow their sodium closely because some patients need salt replacement, hydration, and anti-emetics.

The second [agent approved for triple-class refractory multiple myeloma] is belantamab mafodotin-blmf [Blenrep], which is an antibody-drug conjugate that targets BCMA. The poison is MMAF, which is associated with thrombocytopenia and ocular toxicity. We found that when belantamab mafodotin is used as a single agent without a steroid, the response rate was just over 30%. Patients who respond have durable responses upward of 10 or 12 months. We just have to watch patients for ocular toxicity because [belantamab mafodotin] can cause keratitis on the surface of the eye. Patients must see an ophthalmologist before each dose of belantamab mafodotin, which is dosed every 3 weeks. In my experience, [keratitis] usually occurs after the second or third dose. Most patients respond after the first or second dose, so we can see if the patient responds, and then continue or modify the regimen. We can lengthen the dose out to every 4 weeks or every 6 weeks or drop the dose from 2.5 mg/kg to 1.9 mg/kg.

Lastly, we have a new drug called melphalan flufenamide [melflufen; Pepaxto], which is a lipophilic, alkylator-based therapy. The lipophilic component gets the drug fast into cells, but it can be cleaved off the alkylator by aminopeptidases. In fact, normal cells dont have many aminopeptidases, so [melflufen] gets in and out of normal cells relatively quickly; however, the drug gets in myeloma cells, the lipophilic component is cleaved off, and the alkylator gets trapped inside the cell. [Melflufen] is [administered as] one flat dose of 40 mg every 4 weeks with weekly dexamethasone. It is tolerable; the big adverse effect [AE] is blood count suppression. Weve seen response rates in the 25% to 30% range.

The newest [therapy] on the block in what is available for patients who have had 4 prior lines of therapy is the CAR T-cell therapy ide-cel. It is BCMA directed, the original vector was known as bb2121. It is now FDA approved.

The rollout [of ide-cel] has been a little slow in terms of slot allocation, and it has been difficult for centers across the country to get patients on slots. We are hoping that the slot availability will increase over the next few months.

That said, for patients who are triple-class refractory and have had 4 prior lines of therapy, [ide-cel] is a perfect therapy. The CAR T cells have to be done at a licensed CAR T-cell center, of which there are only about 70 in the United States. That comes with some overhead because patients must move to the center and remain there for the first 30 days of therapy because of the significant toxicities associated with CAR T-cell therapy. [These AEs] are mostly cytokine release syndrome [CRS], which happens 80% to 90% of the time, and some neurotoxicity, which is reported in around 15% to 20% of patients. Patients must be followed closely and require initial hospitalization between 7 to 14 days. Then, patients must stay local [for follow-up].

There is a lot of overhead, but it is a one-and-done treatment. We collect their T cells, give them lymphodepletion, give them back the T cells, and patients are off therapy. The median PFS for ide-cel is about 12 months, so hopefully patients get 12 months of free time where they dont need therapy and have truly good quality of life, which is quite nice.

The nice thing about immunotherapy is that multiple targets are being investigated. BCMA was our first target, but we have others, such as GPRC5D and FcRH5. We have multiple different CAR T-cell therapies currently in research studies to try to build upon ide-cel.

We also have BiTEs, in which one arm binds to BCMA or whatever the target is on the myeloma cell, and the other arm looks for the immune cell in the local environment. Most of the other arms bind to CD3 on T cells to activate the T cells. [BiTEs] are a little bit different in terms of how they bind to the myeloma cell and how much they activate the T cell by binding to CD3.

That said, in the early research, most of these therapeutics as single agents have shown response rates on the order of 60% to 80%. Thats, again, unprecedented for single agents. These therapeutics are quite impressive in terms of response rates, but they are also associated with CRS and mild neurotoxicity. They require initial dosing in the hospital and patients are usually hospitalized for 7 to 10 days for step-up dosing. After that, [treatment] can be done in the outpatient setting with intermittent dosing. BiTEs vary from dosing weekly and then less frequently to every 3 weeks. Coming back to the center every 3 weeks is reasonable, even for patients who live outside the research center.

In San Francisco, we have patients coming in every 3 weeks to get their therapy and then they head back home, which is nice. However, it is ongoing therapy and patients must continue their therapy rather than receive a one-and-done treatment. This is because BiTEs are off-the-shelf products. There is not a collection and manufacturing step. These drugs are going to be given in the community eventually once they are approved. These drugs will be used in many more patients compared with CAR T-cell therapy just because of the logistics of CAR T-cell therapies, so BiTEs are exciting.

These advances [observed in multiple myeloma] have also spilled over to amyloidosis. We now have great frontline therapy for amyloidosis, as well as many irons in the fire [evaluating] ways we can treat relapsed amyloidosis. Weve had a troubled past [with] antiviral therapy in amyloidosis. However, there is renewed interest in this and, certainly, there are patients with amyloidosis who would benefit from antiviral therapy.

There is a lot of work going on in amyloidosis currently. The ANDROMEDA study [NCT03201965] has shown in randomized fashion that daratumumab plus bortezomib, cyclophosphamide, and dexamethasone [VCd] results in better organ response rates and PFS vs VCd alone, which had really been our standard therapy in amyloidosis. Going forward, patients with amyloidosis should receive this quadruplet as frontline therapy.

Patients with amyloidosis also have a high incidence of 11;14 translocations [t11;14]. Some case reports [have read out] of patients being treated with venetoclax. Ongoing research avenues are going to further investigate venetoclax with or without the combination of other drugs. Venetoclax will have a strong response rate in patients with amyloidosis and will be used for initial relapse. Eventually, [venetoclax] might be used in patients with t11;14, but those studies are being done. Approval for that is a long way down the road.

Also down the road for amyloidosis are BiTEs. BCMA is on the surface of plasma cells in amyloidosis, also, [as in multiple myeloma]. There is also a renewed interest in antiviral therapy in amyloidosis. The amyloid proteins deposit in the cell and cause significant organ toxicity, especially in the [heart] and kidneys. Antiviral therapy may enhance and quicken organ responses to improve survival for patients, including those with severe cardiac amyloidosis.

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Emerging Quadruplets, Novel Targets, and Immunotherapy Advances Personalized Medicine in Multiple Myeloma - OncLive

Cardiac Stem Cells Comments Off on Emerging Quadruplets, Novel Targets, and Immunotherapy Advances Personalized Medicine in Multiple Myeloma – OncLive | July 22nd, 2021

After a year under the hatch, this summer 2021, glowing, luminous and radiant is the go-to gorgeous look that American women want !

For whatever face you have to show the world today, moisturizing oil replenishes your skin, repairing damage from UV and boosting your natural glow with an astonishing amount of benefits- which is formulated to re-energize your look as it tones and refines pores. Many viewers have asked my expert advice on the best ways to approach and achieve a dewy summer complexion that will leave skin luminously smooth on the path to corporate ascension during business hours as well as summer social activities.

In the summer, I can simply suggest that less is more. Radiant glow is the way to go with a delicate added dose of a real-to-the-feel modified bronzer and a fresh coral blush. This season, in addition to eating fruits and vegetables. drink lots of water to replenish the skin. Be mindful to get in a sweaty cardio sesh to increase blood flow and that healthy look from within which ultimately surfaces in the face to improve skin texture and tone for a natural radiant complexion.

Protect your skin from the sun:

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Exfoliation is essential for smoothskin. I recommend to exfoliate once or twice a week to remove deadskincells and leaveskin glowing. This season, a unique blend of supercharged ingredients have been expertly formulated to deeply moisturize and restore the skins natural balance, revealing a clear and radiant glow.

If you're looking for a moisturizer with a luminous finish, then read below where I have curated a Forbes list of super-hydrating product offerings infused withtechnicall advanced hyaluronic acidand pearl articlesthat blur, reflect, and enhance your complexion to make you look instantly more radiant than ever!

+ Lux Unfiltered:

For a natural color and glow.

+ Lux UnfilteredNo.12 Bronzing Face Drops is your answer to a bronzed face without the risks of sun exposure. N12 seamlessly integrates into your skincare routine without disrupting your process or products. It is fragrance-free, non-comedogenic, compatible with all skin types, and loaded with antioxidants. Your tan is now customizable, buildable, and most importantly, fake, without looking fake. Recommended to mix with your desired number of drops with your face moisturizer and apply to clean skin.$42

AbsoluteJOI:

The new Daily Hydrating Moisturizing Cream is the first of its kind, a nutrient-rich 2-in-1 tinted ... [+] moisturizer specifically crafted for women of color for everyday use.

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AJ Crimson Beauty:

AJC Universal Finishing Powder in Toasted Cinnamon

AJ Crimson Beauty-AJ Crimson Beauty's Universal Finishing Powders are perfect for all skin tones. Great to use to set your makeup for a Matte or Semi Matte Skin Finish. Can Be Used to set Foundation, Concealer, Contour, Highlight or Tattoo cover! Available in a range of colors including Neutral Matte, Bamboo, Rick Umber and Toasted Cinnamon. $35

Beauty Bakerie:

Swatches of the Beauty Bakerie InstaBake Aqua Glass Foundation in Shades 301N to 325N.

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Bespoke:

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Bespoke-Manuka Honey and Bespokes Potent CBD, infused in one amazing product with an astonishing amount of benefits. The Manuka Honey + CBD cream for hands and body offers you the healing benefits of Manuka honey, the inflammatory and pain support of CBD, plus the soothing, calming properties of menthol extract. Bespoke sources our Manuka honey from New Zealand. But not all Manuka is equal. We source only the purest honey with an Ultra Premium Grade Unique Manuka Factor (UMF) of 15+. Youre getting exceptionally high-quality Manuka along with the superior CBD youve come to trust Bespoke Extracts for. This topical treatment will enhance your skincare regimen. Use sparingly on sore, dry skin, or when experiencing muscle or joint pain. Manuka Honey + CBD Cream will nourish your skin and provide supportive care to soft tissues. $59

Circumference:

The gentle cleanser is powered by olive leaf extract, derived from byproduct harvested in California ... [+] that would otherwise go to waste.

Circumference- The second formula born from the Waste-NotSourcing Initiative - this Daily Regenerative Gel Cleanser is powered by upcycled olive leaves, in partnership with California-made, Brightland. Last fall, Circumference approached the modern essentials pantry brand to take the byproduct - that have no use in the olive oil making process - and slow-extract for bioactive nutrients. After the process was complete and the formula was perfected, mulch was returned to their farms for the following seasons compost - completing the circular economy.$48

CocoBaba:

CocoBaba Coconut Butter Mousse, Coconut Body Oil, and Coconut Oil Scrub.

CocoBaba- CocoBaba is the new all-natural, vegan skincare line for women founded by Emma Heming Willis. CocoBaba was originally conceptualized when Emma was pregnant with her first daughter and was in search for an all-natural coconut oil-based product line to nourish and soothe her skin but could not find one. After 4 years in the making, the brand finally launched earlier this year and while its targeted toward moms and moms-to-be, its great for anyone! As summer approaches and we spend more time outside, its time to pay extra attention to our skin and make sure its nourished and protected to maintain that beautiful summer glow all season long!

All CocoBaba products are made with pure, certified organic coconut oil, and are 100% vegan, dermatologically tested, and completely free of silicones, parabens, and mineral oils. The Coconut Butter Mousse is a natural, effective way to nourish skin with this whipped blend of coconut, chia, sunflower, and jojoba oil. The Coconut Body Oil is silky but never greasy, this natural beauty secret uses 100% raw certified organic coconut oil to lock in moisture. And finally, the Coconut Oil Scrub is an all-natural exfoliant made with real coconut husk and apple seed. $54.99

EiR NYC:

Surf Mud Body Oil

EiR NYC-As with all EiR suncare products, Surf Mud Body Oil is made with 100% Reef Safe Ingredients. Surf Mud Body Oil is a tinted tanning oil with Antioxidant-rich hydrating oil combined with zinc and chocolate to deeply moisturize and increase blood flow to the skin, and enhance your bronze-y sun-kissed look.$35

Elaluz:

Camila never leaves home without her All Day Beauty Water and neither should you keep your skin ... [+] glowing and give it a refreshing boost on-the-go all summer long!

Elaluz -When Elaluz founder Camila Coelho created The All Day Beauty Water she knew she wanted a versatile product she could use throughout the day to keep her skin glowing and nourished. Enriched with Brazilian superfood ingredients like Guarana & Papaya Extracts and Buriti & Bataua Oils, this instant skin boost is formulated to re-energize your look as it tones and refines pores. Use it before makeup to prep, post-application to set, or whenever you need an instant boost of radiance. $49 USD

Hey Dewy:

Get the cutest, facial humidifier today - your skin and hair will thank you for it.

Hey Dewy- Bring this portable USB humidifier with you wherever you go for continual hydration at your desk for work, overnight while you sleep or on-the-go to your dream destination. You can also nourish your skin with Hey Dewy before, after or even during your beauty routine. Our portable facial humidifier is our flagship product that is the foundation of our brand and purpose. It serves as the conduit to wellness via water and humidification, as well as the means to giving 10% to Clean Water initiatives like The Water Project. $39

Hydra Bloom:

Moonshine Coconut Illuminizer helps bring out your inner glow by adding a gorgeous highlight to your ... [+] cheekbones, eyes and decolletage.

Hydra Bloom-This skin perfector suits all skin tones. Made with Coconut and natural shimmering minerals and Vitamin E and Australian Flower Essences this illuminizer will have you glowing. $28.00

James Read Tan:

Tan Easy-to-apply and can be tailored to your liking perfect to achieve that faux post-vacation ... [+] tan while quarantining.

James Read Tan-Concentrated onthe-go multi-vitamin gel tanning drops that you can add to your SPF or moisturizer. Formulated with powerful antioxidants and Vitamin complexes combined with key anti-ageing skincare ingredients to gently brighten, smooth and tan your skin. Formulated to improve the skins natural defense against free radicals, stimulate collagen synthesis and gives you a natural looking glow. Enriched with Vitamin C, Hyaluronic Acid, Aloe Vera, Natural Caramel and self-tan for the ultimate glow.$33

Kura Skin:

Kura Skin

Kura Skin-Kura Skin curates clean, personalized skincare routines just for you. Kura analyzes your age, location, existing product usage, skin types and concerns through a proprietary, high-tech algorithm to build your own skincare routine. Designed for all genders and ethnicities, you wont end up with a drawer full of samples youll never touch, or worse, a product that irritates your skin. Kura only curates nontoxic, cruelty-free, nutrient-dense, effective indie brands for healthy, glowing skin.Individual products starting at $28

lilah b.:

Moisturize, balance and prime with lilah b.s Aglow Priming Oil

lilah b. -A three-in-one serum, moisturizer, and primer that can be worn alone or under makeup creating a smooth, flawless canvas for long-wear makeup application. Aglow Priming Oil is a fast-absorbing, silicone-free priming face oil that nourishes and hydrates skin. Formulated with a nutrient-rich trio of tamanu, jojoba and sweet almond oils to soften, smooth and comfort the skin. Infused with grape seed extract to help improve skin firmness and reduce fine lines and wrinkles. Enriched with purple tea extract to improve skin texture and tone for a natural radiant complexion. The perfect dose of nourishment to prep skin with an effortless glowing finish. $68

Luzern:

Hydrate, soothe and boost luminosity with Luzerns new Alpine Rose Glacial Serum Masque.

Luzern-Infused with precious Ruby Powder, stem cells from the treasured Alpine Rose, a proprietary peptide-ferment, and an abundance of moisture factors and nutrients, this unconventional nectar mask provides instant hydration and calm, leaving skin velvety soft, smooth, and luminous. $150

Madeca Derma:

Madeca Derma Revitalizing Overnight Sleeping Mask

Madeca Derma-This supercharged night mask powered by propolis that helps skin recover overnight for a more youthful look by morning. $27.99

MAKE:

Gently yet effectively cleanses to remove impurities while hydrating and balancing

MAKE Succulent Skin Gream-This serum weight facial cleanser, is a pH-balanced, sulfate-free universal gel that gently cleanses skin, effectively removing dirt, oil and impurities without stripping the skin of essential moisture. Supercharged with amino acid enriched surfactants that preserve the skin barrier. Also formulated with prickly pear, cactus, agave, niacinamide and sodium hyaluronate to provide nutrients. $24

Manna Kadar Cosmetics:

Light up your skin with an all over radiance with Sheer Glow

Manna Kadar Cosmetics-Manna Kadar Cosmetics shimmer lotion works with all skin tones. Mix with foundation, BB cream, or body lotion to create a dewy glow for that radiant and youthful look. Get that extra highlighter look applying to cheek bones and collar bones for a more pronounced look. $29

Miami Beach Bum:

Formulated with oregano, aloe and jojoba to give your skin a full reset.

Miami Beach Bum To our marine scientist founder, self-care means being active and around water. After constantly being in wet bathing suits she developed folliculitis on her bum and was unable to find a natural solution for it. Using her chemistry background, Ayssa crafted our signature Bum + Body Cream with the mission of bringing skin health to the forefront of self-care. Now with a full collection, each product has become an essential part of Ayssas personal ritual and we hope they can become a part of everyone's unique self-care ritual as well. $45

natureofthings:

natureofthings Clarifying Facial Polish combines the purifying action of a cleanser with the ... [+] resurfacing and glow-enhancing benefits of an exfoliant.

natureofthingsClarifying Facial Polish combines the purifying action of a cleanser with the resurfacing and glow-enhancing benefits of an exfoliant. A few drops of water activate the powder into a paste (for a milder formulation, simply add more water). Nutrient-rich lava ash from the Korean island of Jeju and Kisameet Glacial Clay penetrate deep into the skin to draw out impurities and oil, unclog pores and promote overall tightness and tone. Salicylic acid, lactic acid and papaya enzyme work gently to slough off dead skin cells responsible for dull complexions and uneven texture. Colloidal oatmeal and olive oil powder soothe and moisturize. Skin looks smooth, refreshed, and primed to absorb any subsequent products. $65

No, Thank You:

An Oil For All Day

No, Thank YouFor whatever face you have to show the world today, our moisturizing oil replenishes your skin, repairing damage from UV and boosting your natural glow. Use it as often as you like, as a little extra help to welcome all the different emotions and expressions you need to communicate every day. Our vitamin C perfectly encapsulates our approach to skincare, specifically our commitment to making sure every ingredient really earns its place in the bottle formula over fads if you will. Vitamin C is an amazing ingredient but that doesnt mean you can just add it to a product and call it a day. You have to think about quality, concentration and combination. We use a shelf-stable form of vitamin C, in the right amount (sometimes more isnt more), combined with CBD and other ingredients that enhance its effectiveness. Its a holistic approach to skincare formulation that has become the hallmark of NTY products. $85

Nourishe:

Nourishe Glowing Skin Serum

Nourishe-This waterless, gentle facial oil to help balance breakout-prone and sensitive skin. The rich blend of 32 botanicals gives you a smooth, energized complexion, boosting skin's collagen production and elasticity at the same time. The product comes in biophotonic glass, with minimal plastic packaging to maintain potency. $24.50

Obagi Clinical:

Exfoliate, smooth and retexturize skin with the Obagi Clinical Blue Brilliance Triple Acid Peel

Obagi Clinical-This is a one-of-a-kind facial peel that combines three potent acids to exfoliate, smooth and retexturize the skin for a more radiant-looking complexion. This powerful, award-winning at-home peel utilizes the strength of salicylic, glycolic and lactic acids to help minimize the appearance of uneven skin, reveal a brighter-looking, more youthful look, and keep pores clean. The self-neutralizing at-home peel is a 2-month series and comes with four 8mL vials - one to be used every two weeks - for a gradual peel with no downtime. $145

Obakki:

This gift set is the ultimate recipe for silky, moisturized skindeeply nourishes, restores, ... [+] soothes and helps lock in moisture. A definite favourite for all skin types.

ObakkiObakki is a purpose-led lifestyle brand that connects people through handcrafted products and artisan ware. The Moisturizing Gift Set in Earthy Scent features a deeply moisturizing trio set of Nilotica Shea Butter, Whipped Shea Lotion and the Obakki Organic Sugar Scrub. The Earthy Scent is an invigorating blend of cedar, ho wood, and grapefruit, and is a definite favourite for all skin types. All Obakki skincare products feature 100% all-natural ingredients and never contain palm oils, artificial fragrance or colourants, parabens, sulfates, or animal products. $76 USD

One Ocean Beauty:

To use, close eyes and spray hydrating mist all over the face 3 times a day

One Ocean Beauty-This refreshing mist is designed to protect against photoaging from blue light exposure. It works to repair damage, hydrate and restore skin's natural barrier to protect from urban pollution. $58

Original Hemp:

Try Original Hemp's Topical Cream to reduce inflammation and keep skin hydrated.

Original HempInfused with Organic coconut oil, argan oil, shea butter, full-spectrum hemp extract and 10+ botanicals our natural Original Hemp's Topical Cream will give a natural soothing relief while absorbing on contact. It leaves skin feeling soft, smooth and hydrated; never greasy. Cream may increase antioxidant activity and reduce free radical damage, support skin healing and protection, reduce signs of aging (wrinkles, lines, scars, damage), improve skin health and appearance. $65.99

PRESSOLOGY:

PRESSOLOGY's GOLDEN HOUR, an Ayurvedic botanical serum with a rich source of antioxidants, vitamins, ... [+] and minerals to enhance your natural glow.

PRESSOLOGY- PRESSOLOGYs GOLDEN HOUR is a multi-purpose botanical serum carefully formulated with an exclusive caliber of Ayurvedic ingredients to heal and enhance the skin's long-term health. GOLDEN HOUR is infused with seven USDA organic and vegan cold-pressed oils, making it a rich source of powerful antioxidants, vitamins, and minerals that work to restore, repair, protect, and hydrate the skin. It's packed with vitamins A, B-complex, C, D, E, and F to stimulate fibroblasts, reducing fine lines and wrinkles while correcting skin tone and texture. Naturally occurring minerals like copper, iron, and selenium work to reduce hyperpigmentation and neutralize free radical damage. This plant-based serum is suitable for all skin types and versatile enough to be applied on the scalp and cuticles to encourage strong hair and nails.$38.00

Pseudo Labs:

Accentuates and highlights the natural beauty of the face with the PHreckles Kit.

Pseudo LabsPHreckles is a vegan, hypoallergenic, gluten free, cruelty free & water resistant faux freckle cosmetic that accentuates and highlights the natural beauty of the face. PHreckles melts into skin and blends with your natural complexion with almost zero effort and washes away with your daily cleanser. PHreckles Kits include a 4.3 ml PHreckles fill, a faux leather pouch and a custom Pseudo Labs pick for perfect application.$38.00

ROEN:

REN products combine a fashion-forward, innovative, glamorous approach with clean, ethical, ... [+] high-performance ingredients.

ROEN -Celebrity Makeup Artist, Kate Synnott, curated this Mothers Day Limited Edition Set your mom will absolutely love. This rosy inspired set is perfect for the mom who gravitates towards warm and cool pink tones. The 11:11 Eyeshadow Palette consists of cool hero tones designed for everyday where; Situation (soft pink), Hashtag (taupe green), Ciao! (deep fuschia), Rosie (petal pink). The Kiss My Liquid Lip Balm in Remi is a glossy nude liquid lip balm that provides the high shine of a gloss and the benefits of a balm. Disco Eye is a universally flattering eyeshadow that can be worn alone or applied as a topper to elevate and enhance your favorite shadow. Lastly, their avocado oil infused CAKE Mascara is hydrating mascara that volumizes, lengthens and lifts. $100 ($125 value)

Smashbox:

Smashbox Halo Healthy Glow All-In-one Tinted Moisturizer Broad Spectrum SPF 25

SmashboxPrimer-powered for all-day wear & a healthy glow, this all-in-one, SPF tinted moisturizer gives you lightweight, natural-looking dewy coverage that hydrates skin for up to 24 hours. It primes, perfects, protects & hydrates in one easy step. The breathable, vegan & oil-free formula is boosted with 81% skin-caring ingredients that moisturize, condition & protect. It has rose extract, hyaluronic acid, niacinamide, goji berries, gold & peptides. $36

Summer Fridays:

A shimmering blend of nourishing oils that illuminates skin for a light, sunkissed glow and is ... [+] gently scented with a warm, summertime fragrance

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Here's How To Get The Perfect Summer Skin Glow In 2021 - Forbes

Skin Stem Cells Comments Off on Here’s How To Get The Perfect Summer Skin Glow In 2021 – Forbes | July 7th, 2021

Keila Torres knew during a conference trip to Florida she was going to meet the woman who saved her life. What she didn't expect was to see someone so familiar.

Torres, 44,of Worcester, Massachusetts,desperately needed a bone marrow transplant in 2016, when she was 39, to beatacute myeloid leukemia, a cancerthat starts in the bone marrow but often moves into the blood.

A bone marrow transplant isa treatment option for people withblood cancers, such as leukemia, and it replacesunhealthy blood-forming cells with healthy ones from a donor, according to Be The Match, a nonprofit that pairs peoplewith a donor.

She had slightly less than a 50% chance, according to Be The Match. But she beat thoseodds, thanks to Palm Desert resident Odalis Trinidad.

When the two women met on June 23, Torreshad a realization. Her body had been changing since the transplant, and now it started to make sense.

"My blood type changed to Odalis blood type.I developed allergies after the transplant, and she has allergies," Torres said. "Her hair is long, beautiful and really curly, and when my hair started to grow back, it was very curly, very tight curls. When I saw her, I was like, 'Wow, that's why my hair is like that.'"

"You basically become your donor. She lives in me," she added.

Dr. Ayad Hamdan, a bone marrow transplant specialist and board certified hematologist with the Eisenhower Lucy Curci Cancer Center, explained that since new stem cells from adonor replace the stem cells in a patients bone marrow, which is the "factory of our blood cells," the patient will have the same blood type as the donor.

He added it is possible for patients to develop allergies, and"most patients who receive chemotherapy or a transplant have the experience that their hair may grow back with a different texture," but the hair follicles themselves don't change.

Not only do the two women share hair textures and occasionally stuffy noses, they're driven by their desire to inspire others to help those in need.

Most 19-year-oldsare focused on having good times with their friends, not necessarily providing life-saving donations.

Trinidadsaid she tried to donate blood as often as she could, even though the process was always a bit uncomfortable either her arm would stop pumping enough blood, or her arm would be too sensitive. During one of her visits, she noticed a poster for Be The Match and decided to do some more research.

The process to join the donor registryseemed "really easy" for Trinidad, now 24.She received a registration kit to give a swab of cheek cells and sent it back in October 2015. Then camethe waiting period.

"If you get called, you get called; if you don't, well, at least you tried, right?" the Palm Desert resident said.

People between the ages of 18 and 44 can join the Be The Match donor registry. Cells from younger donors have the best chance of successful donations, according to the Mayo Clinic.

Due to a lack of diversity on the donor registry, white patients have a better chance of finding a match on the registry than do people of other races. According to the site, African Americans have a 29% chance, Asians and Pacific Islanders 47%, Latinos 48%, Native Americans 60% and whites 79%.

In July 2015, Torres, 38 at the time, learned she was diagnosed with Stage 3 breast cancer. With two young sons, ages 15 months and 5 years old at the time, she knew she had to fight to be there for her boys. After chemotherapy, radiation, lymph node removal and a bilateral mastectomy, she was declared cancer-free a year later.

The good news, unfortunately, was spoiled in September 2016.

"I felt like I was fine. I was recovering, I was spending time with my kids, I was going to work, my hair was growing back and I felt great," Torres said. While undergoing a bone marrow biopsy, she was told "there was something wrong" with routine lab work.She remembered asking her oncologist, "What's the worst that could happen?"

"If we find leukemia," Torres recalled her oncologist saying. "When I heard leukemia, I was like, 'Oh,that's not going to be me, it's probably something else.'"

But the biopsy showed she hadacute myeloid leukemia. It isa common type of leukemia in adults, although it accounts for just 1% of all cancers,according to Cancer.org.It is also generally uncommon to find in people younger than 45. Torres was 39.

"I was in shock. I was devastated. I had already gone through so many things," Torres said, "but in the back of my head I was thinking, 'I've been through breast cancer, I can do this.'"

But the gravity of the situation didn't hit her until she met the leukemia team at Massachusetts General Hospital. Walking into one of the clinic rooms, she remembers feeling "very claustrophobic,"like she was "running out of breath."

Torres began chemotherapy atMassachusetts General, but to have a betterchance at beating leukemia, she would need a bone marrow transplant.

The two women had plenty in common even before the transplant,Torres said, almost as if Trinidad was always her"missing puzzle piece." They both have birthdays in October, mothers from Guatemala (Torres grew up there as well) and they're both mothers.

The best match for a bone marrow transplant is when a patient and donor'shuman leukocyte antigen closely match. HLA"is a marker on our stem cells thatdetermines how our immune system responds," explained Hamdan. Those markers are used by an individual's immune system to know which cells belong in the body and which ones don't, according to Be The Match.

Doctors first looked to Torres' brother to see if he was a match. Siblings have a one in four chance of being a match since half of an individual's HLA markers are inheritedfrom their mother and the other halffrom their father, according to Be The Match. About seven out of 10 people won't have a close match with a family member, as was thecase with Torres. That's when people look to thedonor registry.

After Trinidad completed her cheek swab in October 2015, she essentially forgot about it since she didn't hear back from the registry. She received a phone call a year later.

"'Hey, I don't know if you remember you signed up for this, but this is what we do and we're calling to let you know that you have a possibility of saving someone's life,'" Trinidad recalled hearing.The only information she was given was the person needing the donationwas a female, 40 years old (Torres turned 40 in October 2016) and the type of leukemia. Nothing more, not even a name.

So, yes or no? It wastime to decide.

"I called them (the next day to learn) what did I need to do, what did they need from meto make sure it could be successful," she said.

Trinidad had blood work and other tests done prior to donation day. Her family was very supportive of her decision to help save a life, she said, whileit was a bit "hard for my friends to be on board."

"We were all 19, so they were like, 'You're crazy, you don't even know them and you're going to have this whole surgery for them?'I was like, "Well, yeah, I can save someone's life,'" Trinidad recalled. "You would want someone to do it for you, so how could you not do it?"

On donation day, donorsare put undergeneral anesthesia and marrow cells are taken from the back of the pelvicbone.

"The donor lies face down, and a large needle is put through the skin and into the back of the hip bone. Its pushed through the bone to the center and the thick, liquid marrow is pulled out through the needle," according to Cancer.org.Around 10%, or 2 pints, of marrow are collected, and the procedure takes up to two hours. The donor's body replaces those cells within four to six weeks.

Trinidad described the day in December 2016 as "nerve-racking,"but not because of the giant needle.

"I know everything that they're doing to me, but I can't, I literally cannot, know her perspective, what she is going through, how it is going to get to her," she said. "During this whole procedure, I'm nervous, I'm thinking, 'I hope it works, I hope it works.'I'm a match, but her body might not (accept the cells)well. I want to be sure that I'm doing the best I can so that it's the best for her."

To begin the transplant process, a receiving patient must undergo a conditioning regimen, which includes chemotherapy and sometimes radiation, to "wipe out" their immune system and leukemia cells, according to Hamdan.On transplant day, also called Day Zero, patients receive the donated cells through a blood transfusion.From Day Zero onward, the donated cells grow and make new blood cells, which is called engraftment, according to Be The Match.

Torres, admitted to the hospital on Thanksgiving, had a week straight of chemotherapy. Day Zero, which she considers one of her birthdays and her "rebirth," was Dec. 2, 2016.

It's normal for patients to feel weak, and Torres remembers being "sick to my stomach" the first few days after the transfusion. But her red and white blood counts started growing, she said, and slowly started feeling better. She was released from the hospital on Dec. 23, just in time for the holidays.

Both women had played a big part in each other's lives, and yet they still didn't know anything about one another.

Transplant recipients and donors have to wait one year before they can have direct contact with each other in the United States, according to Be The Match.

"This could only work if both of us want to know," Trinidad said."It was hard because I wanted to know her recovery, I wanted to know if it worked. What if it didn't work and they just didn't tell me anything at all?"

By the time the one-year mark came, the two women were ready to know something, anything,about each other.

It was an instant connection, almost as if they had known each other their entire lives, they both said. Finallyconnected on Facebook, they could get a glimpse of the other's family and see what they were up to. They talked and texted whenever they could.

It wasn't until a few weeks after their initial contact that Torres revealed to Trinidad that doctorsfound leukemia once again in January 2018.Torres would have to go through the transplant process all over again, but this time witha different donor.

Hamdan explained: "Transplants are most of the time the only chance for patients to be cured, and although there is a good chance of success, the cancer can come back. (It) depends on the disease, the age of the patient, the type of transplant."

Torres still wouldn't change a thing.

"She gave me life the first time around. I was able to come home and be with my kids for a year," Torres said. "Even if I had relapsed or not, Im so grateful for her for doing an act of kindness. At 20,Iwasnt thinking about stuff like that."

Trinidad, now a mother herself to3-month-old son Jimmy,said having her own child put thedonation into a whole new perspective.

"I really just am happy to give her that time with her kids. I now know how important and valued that time is," she said.

But thatwasn't the end of the journey.

They both had meeting each other in-person on their bucket lists, and when an opportunity came at aHOSA Future Health Professionals convention last month in Orlando, Floridaboth said "it was meant to be."

Representatives from Be The Match reached out to the two women and asked if they'd want to share their story to the students attending the conference. Trinidad was also a member of HOSA when she attended Palm Springs High School.

After years of texting, calling and social media lurking, they hugged on stage at the conference for quite a long time, admitted Trinidad, and "neither of us wanted to let go." She describedthe moment as "surreal,"finally seeing "the life that I gave her."

And for Torres, to see the woman who went froman anonymous lifesaver to a dear friend and a bit of a look-alike,saying thank you in-personis a moment she'll never forget.

"Theres no way that Iwill ever be able to repay her because theres no price with what she did," Torres said. "Im think I'm still kind of digesting all the emotions that came with it, but the one thing I know isIm full of gratitude for what she did for me.

Trinidad hopes more people will join the donor registry "it's so easy," she reiterated and be there to answer the call if they end up being someone's best match.

"I'm a donor because I wanted to be one," Trinidad said. "I know it required me physically giving up some bone marrow, but itsaved someones life, and I would do it again."

Torres, too, can attest to that: "If it hadnt been for her the first time around, honestly I dont think Iwould be here."

HOW TO JOIN THE BE THE MATCH REGISTRY

Visithttps://bethematch.org/to learnhow to join the registry, request a cheek swab and what the next steps are if you're a match.

Ema Sasic covers health in the Coachella Valley. Reach her at ema.sasic@desertsun.com or on Twitter @ema_sasic.

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Palm Desert resident meets the woman whose life she saved with bone marrow transplant - Desert Sun

Skin Stem Cells Comments Off on Palm Desert resident meets the woman whose life she saved with bone marrow transplant – Desert Sun | July 7th, 2021

A year before the pandemic, I was diagnosed with a condition called mast cell activation syndrome (MCAS). A hallmark of the syndrome is hypersensitivities in more than one organ system: Food and other triggers can give me abdominal pain and severe diarrhea; my nose swells and I sneeze and wheeze. That sounds like allergies, but I've never tested positive on an allergy test.

Mast cells are among the immune system's first line of defense. They are abundant in the parts of the body that have close contact with the outside world, including the skin, airways, and intestines. Mast cells gone wrong cause allergic symptoms, secreting histamine and giving us itchy eyes, hives, and rashes. Less well understood is their role in modulating the responses of other immune cells. Before the pandemic, researchers had suggested that mast cell dysfunction could explain severe cases of the flu and highlighted the cells' role in shutting down inflammation in a variety of situations. In my case, probably because of a genetic peculiarity, my mast cells overreact.

I was fairly stable on my medication, and then I became sick with Covid-19. Months after the virus had passed and I no longer had pneumonia, I was still fighting fatigue and breathlessness. My symptoms also flared up erratically. On some mornings, for example, the oatmeal I had relied on for years could cause me abdominal pain. "Once the mast cell response is turned up, it doesn't wind down just because the infection is gone," explained my doctor, Leo Galland, a New York internist who specializes in difficult cases.

MCAS often seems to first emerge after a virus. Could it explain any of the symptoms of the growing group of patients with long Covid? Congress has now dedicated more than a billion dollars towards research into why so many post-Covid patients roughly a quarter, more often women still feel ill long after their infection. In Facebook groups and elsewhere, people with plausible symptoms for instance, severe lingering rashes and months of hives have been trading information about remedies for the disease. Severe fatigue after exercise suggested myalgic encephalomyelitis/chronic fatigue syndrome, which some say is linked to MCAS. Others became lightheaded when they stood up, which might mean they had postural orthostatic tachycardia syndrome (POTS). Spend an hour searching online, and you'll find papers saying POTS, too, may be a manifestation of MCAS.

But getting a workup for the syndrome can be a long ordeal. The full range of tests and treatments aren't routinely covered by insurance, leaving some patients to pay thousands of dollars out of pocket. Before you get there, you need to find a sympathetic doctor: Researchers don't agree on whether the illness is rare, or quite common.

I was lucky; Galland took me on in the 1980s. Long before the microbiome became a news item, he diagnosed me with intestinal dysbiosis a disturbed gut. We don't know why I got sick when I did, but when I showed up in Galland's office, I was a young woman on an absurdly limited diet with a myriad of fluctuating symptoms. On a trip to Tucson, as just one example, my face and arms ballooned, and then shrank on the plane home. I had been exposed to a fungus in the desert. My grandmother commiserated; when her face swelled up, her doctors in Antwerp, in the 1930s, pulled out all of her teeth. She had no explanation.

Interestingly, disturbances in the gut may be linked to severe Covid-19, and correcting them a possible path to health for long Covid sufferers. Mast cells may have a unique role in communicating with gut bacteria. In midlife, I fit the profile for irritable bowel syndrome (IBS), the abdominal pain, often accompanied by diarrhea or constipation, that afflicts as much as 20 percent of the population, and often sets in after a virus. Desperate, in 2018, I had just completed a trial of hypnotherapy for IBS when my digestion took an embarrassing turn, with accidents in taxis, and I could no longer eat outside my home.

A new dietician, Tamara Duker Freuman, author of "The Bloated Belly Whisperer," helped me identify the worst offenders: foods that are high in histamine, which can be found in everything from alcohol to avocados. After further testing, Galland put me on a regime: an arsenal of mast cell modulators and anti-histamines, including Pepcid, which also blocks histamine.

And I got better.

* * *

Mast cells were first named in 1878 by a German-Jewish Nobel Prize winner, Paul Ehrlich, a father of modern immunology who is most famous for discovering the cure for syphilis. At the turn of the century, scientists discovered anaphylaxis, the classic mast cell allergic reaction. The word comes from the Greek ana (against) and phylaxis (protection). The idea that an immune response could actually hurt us, rather than protect us, came as shock. Current research about the gut and immunity may change the paradigm again.

Five decades later, in 1949, scientists described a rare genetic disorder called mastocytosis, in which mast cells produce clones, building up in the skin, bones, and other organs. It wasn't until the 1980s that researchers began to notice that mast cells could become hyper-responsive or over-activated without cloning.

On a separate track, since the 1990s, researchers have explored mast cell activity in IBS. (A clinical trial of Pepcid and Zyrtec for difficult IBS cases is currently underway at the University of Cincinnati.) Kyle Staller, director of the Gastrointestinal Motility Laboratory at Massachusetts General Hospital, now sometimes prescribes Pepcid if he sees other signs like hives, to patients who ask him to consider a histamine or MCAS issue. "I think anyone who's been following the science closely has to start wondering, 'How much could this be playing a role in that IBS patient who's in front of us on a given day?'" he told me.

Competing proposals for diagnostic criteria emerged after 2010. Both proposals say that doctors should rule out other explanations for a person's symptoms, and that symptoms should appear in a least two organ systems (in my case, it affects my gut, nose, and skin). Both proposals require lab tests but they disagree on which tests are necessary, and on the ranges that would indicate someone has MCAS, as well as other details. Because lab results are elusive, Galland and some other doctors rely on a medical history instead.

The disagreement has led to two camps. In camp one, the condition is rare; in camp two, it occurs in up to 17 percent of the adult population. Specialists in camp one say patients are misled: "More and more patients are informed that they may have [mast cell activation syndrome] without completing a thorough medical evaluation," an international group of 24 authors, led by Peter Valent, a hematologist and stem cell researcher at the Medical University of Vienna, wrote in April 2019 in the Journal of Allergy and Clinical Immunology.

A year later, a largely American group of 43 authors led by Lawrence Afrin, one of the earliest mast cell activation researchers, countered in the journal Diagnosis that patients are suffering and even dying from underdiagnosis. By then the pandemic had arrived, and Afrin suggested that some patients with long Covid might be experiencing MCAS.

Patients were seeing links as well. For example, the distinct POTS symptom of extreme lightheadedness, once often dismissed as a problem of anxious young women, emerged as one of the odder long Covid symptoms. POTS, which has been reported by patients who experienced Lyme and other infections, may involve histamine and several other chemicals released by mast cells. It is known to overlap with MCAS.

Last fall, when the Centers for Disease Control and Prevention reported on what it labeled multisystem inflammatory syndrome (MIS), the name rang bells: MCAS is clearly a multi-system inflammatory syndrome. Theoharis Theoharides, a professor of immunology at Tufts University who has studied mast cells for more than 40 years, wrote that MIS patients should be evaluated for MCAS.

Mariana Castells, director of the Mastocytosis Center at Brigham and Women's Hospital in Boston, told me in an email that she's seen no data showing that long Covid patients have the requisite diagnostic markers of MCAS.

Observers agree that the long Covid group probably includes people with different vulnerabilities. It would be marvelous indeed, if, one day, we found a single powerful concept to understand post-viral illness.

In the meantime, you might not need to fit either group's criteria for MCAS, a difficult and chronic illness, to experience your mast cells' betraying you sometimes. "Like many, many conditions, over time we [may] learn that there's a spectrum of disease," Staller said. "It's not an all or nothing phenomenon."

Even the group that sees MCAS as rare acknowledges the existence of a less severe form of mast cell activation that does not meet MCAS criteria. Theoharides has detailed several categories of the illness. He told me that he'd guess half of patients diagnosed with IBS might have mast cell activation of some kind.

If mast cell dysfunction is truly common, I trust the online buzz to help us find out. Crowdsourcing on patient forums is here to stay. And it's good, after all, that sick people shared information, found support, and made long Covid a "thing" with ontological status.

Growing up, I had wondered if my grandmother's multiple "allergies" were real. We didn't laugh, but we didn't exactly believe her. Then it happened to me.

* * *

Temma Ehrenfeld is a writer and ghostwriter in New York drawn to philosophy and psychiatry. Her most recent book is "Morgan: The Wizard of Kew Gardens."

This article was originally published on Undark. Read the original article.

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Immune system mutiny: mast cells and the mystery of long COVID - Salon

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The Body Shop discount codes are hard to come by, but when they *do* rear their beautiful heads (read: now - keeping scrolling), there's one product I always make a beeline for.

We're all well aware of the fact that we should be wearing face SPF every single day at this point. Stat. It's non-negotiable. Even when the weather is as grey and drizzly as it is this July. Sob. But which one? I've got a few on rotation - from Glossier's Invisible Shield to Ultra Violette's Queen Screen Luminising Sun Serum - though my most-reached for is The Body Shop's Skin Defence Multi-Protection Lotion SPF 50+ PA++++. It's really, really good.

A fan favourite for good reason, it's a 2-in-1 moisturiser and SPF 50+ product that helps to protect against pigmentation and premature ageing. On the hydration front, it has been newly formulated with red algae extract and vitamin C to help your skin look brighter and healthier. It's also super lightweight, fast-absorbing and non-greasy, so you don't feel like your face is caked in gloopy sun cream.

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The Body Shop Discount Codes: 15% Off Everything - GLAMOUR UK

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An immunotherapy based on supercharging the immune system's natural killer cells has been effective in treating patients with recurrent leukemia and other difficult to treat blood cancers. Now, researchers at Washington University School of Medicine in St. Louis have shown in preclinical studies conducted in mice and human cells that this type of cell-based immunotherapy also could be effective against solid tumors, starting with melanoma, a type of skin cancer that can be deadly if not caught early.

The study is published June 29 inClinical Cancer Research, a journal of the American Association for Cancer Research.

In recent years, an immunotherapy called immune checkpoint inhibitors has revolutionized treatment for advanced melanoma. In one well-known example, this immunotherapy was successfully used to treat former President Jimmy Carter, whose melanoma had spread to his liver and brain.

But the therapy only works in about half of such patients. And even among those who respond well to the initial therapy, about half go on to develop resistance to it. Consequently, researchers have been seeking different ways to harness the immune system to attack melanoma cells. One possibility is to use natural killer (NK) cells, a part of the immune system's first line of defense against dangerous cells, whether cancer cells or invading bacteria.

Todd A. Fehniger, MD, PhD, a professor of medicine, and his team have had success in clinical trials treating recurrent leukemia with a patient's own natural killer cells or those from a donor. The NK cells are harvested from the patient's or a donor's blood and exposed to a set of chemical signals called cytokines that activate the cells and prime them to remember this activation. When these "cytokine-induced memory-like" NK cells are given to the patient, they are more potent in attacking the cancer because they already have been revved up, as Fehniger puts it.

"These 'revved-up' memory-like NK cells attack blood cancers quite well," said Fehniger, the study's co-senior author and an oncologist who treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. "But relatively little work has been done on whether these cells can be used against solid tumors. This is an unmet need in solid tumor oncology. Our study provides proof of principle that memory-like NK cells respond better than normal NK cells against melanoma, and it serves as a stepping stone to a first-in-human clinical trial of these cells in advanced melanoma."

Added co-senior author Ryan C. Fields, MD, the Kim and Tim Eberlein Distinguished Professor of Surgical Oncology: "We hope this is also a step toward harnessing NK cells against multiple solid tumors. Melanoma was a good place to start because we know it responds to immune therapy. But because many patients don't respond or develop resistance, we felt that targeting a different aspect of the immune system was a promising strategy to pursue."

The standard checkpoint inhibitor immunotherapy that works well in some melanoma patients targets T cells, another type of immune cell that also frequently is harnessed against different forms of cancer. According to the researchers, patients who don't respond well or stop responding to the T cell-based standard therapy and have no other options would be good candidates for NK cell therapy.

The researchers studied human NK cells from both healthy people and from patients with melanoma and found that the cytokine-induced memory-like NK cells could effectively treat mice harboring human melanoma tumors. Tumors shrank to the point of being almost undetectable in many of the mice, and the memory-like NK cells prevented the tumors from returning in most cases for the duration of the 21-day experiment. While normal NK cells also reduced and controlled melanoma tumors, they did not do so to the same degree.

"We are currently designing a clinical trial to evaluate these NK cells in patients with advanced melanoma who have exhausted all other treatment options," Fehniger said. "We would like to investigate NK cells from a donor and, separately, a patient's own NK cells to see if the cytokine-induced memory-like NK cells offer an effective treatment option for patients with this aggressive skin cancer."

The NK cell-based immunotherapy is potentially safer than other cell-based immunotherapies because the NK cells do not trigger a cytokine storm, as is seen sometimes in CAR-T cell therapy, which often is used for blood cancers, nor do the NK cells cause graft-versus-host disease, which sometimes follows a stem cell transplant.

"Even 10 years ago, we had no effective therapies for advanced melanoma -- much like the lack of therapies for glioblastoma or advanced pancreatic cancer today," said Fields, a surgeon who treats patients at Siteman. "Checkpoint immunotherapy has revolutionized melanoma treatment, but we're still not satisfied with the 50% response rate. We want to do better, and this NK cell therapy is a promising approach. And in the future, we may be able to combine an NK cell-based therapy with checkpoint inhibition for an even better response."

Fehniger and his colleagues have worked with Washington University's Office of Technology Management to license the cytokine-induced memory-like NK cell technology to a company called Wugen. Fehniger is a co-founder of Wugen and serves on its scientific advisory board.

Reference:Marin ND, Krasnick BA, Becker-Hapak M, et al. Memory-like differentiation enhances NK cell responses to melanoma. Clin Cancer Res. 2021. doi: 10.1158/1078-0432.CCR-21-0851

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Cell-Based Immunotherapy May Be Effective Against Melanoma - Technology Networks

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The first paper, titled PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress, takes a look at the effect of inflammation on the transcription factor PU.1 and its effect on the production of hematopoietic stem cells (HSCs), or the immature cells found in the bone marrow that can turn into blood cells, according to the study author James Chavez, BS.

Second corresponding author Eric Pietras, PhD, CU Cancer Center Member, said the research from Chavez challenged his previous understanding of how inflammation impacts HSCs.

We thought that introducing a proinflammatory cytokine like Interleukin (IL)-1 would make hematopoietic stem cells proliferate, because when you have inflammation, the body typically interprets it as a signal to produce more white blood cells to fight off an infection or injury, Pietras said, in a CU interview.

However, he and his team discovered that in the presence of IL-1, genes that control the creation of additional hematopoietic stem cells were turned off rather than on, specifically genes related to the synthesis of proteins, were the key of building new cells. I think some of the best science is that which disproves your own notions and dogmas, Pietras said in the CU interview.

The team ended up finding a transcription factor called PU.1 that represses protein synthesis genes in HSCs during periods of inflammation.

That made us wonder what would happen if we got rid of PU.1, Pietras said in the CU interview. He and his team used genetic mouse models that reduced the amount of PU.1 in the HSCs or remove it altogether, uncovering that when PU.1 is reduced or removed, inflammation caused by the introduction of IL-1 triggers the proliferation and expansion of HSCs.

Our findings point to an interesting mechanism for how inflammation can trigger differences in cell fitness when normal HSCs have to compete with HSCs harboring oncogenic mutations that are known to disable or reduce PU.1, Pietras said in the CU interview. In this case, those PU.1- deficient HSCs act like normal cells as long as there's no inflammation. But as soon as you trigger an inflammatory response, it's like throwing gasoline on a fire. The HSCs with loss of PU.1 expand because there is no longer a mechanism to turn their protein synthesis off. And when that happens, you get uncontrolled growth of the PU.1-deficient hematopoietic stem cells, which can eventually lead to leukemia, a type of blood cancer.

The second paper, titled Chronic interleukin-1 exposure triggers selection for Cebpa-knockout multipotent hematopoietic progenitors, co-led by DeGregori and Pietras, looks at the impact of the proinflammatory cytokine IL-1 on hematopoietic stem and progenitor cells (HSPCs).

One of the primary goals, according to DeGregori, was to better understand the factors that determine what kind of mature blood cells are produced from our blood stem cells, or the HSPCs, in response to chronic inflammation. Mouse models were studied by injecting with IL-1 to copy an infection and cause inflammation. This action impacted blood cell production towards making granulocytes, which is a type of white blood cell that helps the immune system fight infections, according to the study authors.

The team also found that inflammation seemed to alter selection in the HSPCs toward oncogenic mutations of the Cebpa gene that are often found in leukemia.

"Our data would suggest that old age, and the inflammation associated with it, could contribute to the increased leukemia rates that occur in the elderly, DeGregori said in the CU interview. For every good process that happens in your body, such as fighting infection, there can also be adverse reactions that create risk. And we think inflammation creates some level of risk, particularly if it's a chronic situation.

DeGregori added that the most widespread cause of inflammation is old age, and examples of conditions that could cause long-term inflammation include arthritis and chronic infections, such as colitis.

"When we get old, many of us become chronically inflamed, DeGregori said in the CU interview. Not everyone experiences the same level of inflammation, but higher inflammation tends to coincide with worse outcomes for people. Our data would suggest that old age, and the inflammation associated with it, could contribute to the increased leukemia rates that occur in the elderly, particularly acute myeloid leukemia (AML).

DeGregori and Pietras note that solving this issue is more complicated than wiping out inflammation altogether.

Inflammation is critically important for surviving infections, DeGregori said in the CU interview. Over evolutionary time, dying from infection was a major risk, so we evolved inflammation as a mechanism to avoid that. On the other hand, we've shown that chronic inflammation could promote selection for oncogenic events, such as through inhibition of Cebpa.

According to Pietras, the next step is to apply these findings to human biology.

I think there are a few different implications for the work, Pietras said in the CU interview. One is that we're learning more about when and where stem cells first gain mutations and the extent to which inflammation can impact the capacity of these mutant HSCs to eventually initiate leukemia. What this tells us is that if we can intervene at an early stage, we may be able to reduce the risk of getting blood cancer.

The studies helped to show that both preventive measures for those at higher risk of developing cancer and treatments for those who are already diagnosed could potentially be improved by addressing bad inflammation while maintaining the immune systems ability to function, according to study authors.

"We don't want to limit someone's risk of getting leukemia and at the same time increase their risk of dying from an infection, DeGregori said in the CU interview. But the more we learn about it, the better we might get at finding that happy balance.

REFERENCE

Gleaton V. Two Studies by CU Cancer Center Researchers Explore Link Between Inflammation and Leukemia. University of Colorado Cancer Center. Published June 28, 2021. Accessed July 1, 2021. https://news.cuanschutz.edu/cancer-center/two-studies-inflammation-and-leukemia

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Chronic Inflammation Can Serve as A Key Factor in The Development of Leukemia, Other Blood Cancers - Pharmacy Times

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Background

Lymphoid non-T cells that can kill virally infected and tumor cells were described more than four decades ago and termed natural killer (NK) cells.1 NK cells can attack tumor cells without priming and their activity depends on a range of stimulatory and inhibitory receptors.2,3 NK cells comprise about 515% of the human peripheral blood mononuclear cells (PBMCs) and are part of the native immune system that screen cell membranes of autologous cells for a reduced expression of MHC class I molecules and increased expression of cell stress markers.4,5 NK cells mediate the direct and rapid killing of freshly isolated human cancer cells from hematopoietic and solid tumors.6,7 (Figure 1) NK cells in human peripheral blood, bone marrow and various tissues are characterized by the absence of T cell receptors (TCR) and the corresponding CD3 molecules as well as by the expression of neural cell adhesion molecule (NCAM/CD56).8 Human NK cells are generated from multilineage CD34+ hematopoietic progenitors in the bone marrow and their maturation occurs at this site of origin as well as in the lymphoid organs but not in thymus.9 In blood, NK cells show a turnover time of approximately 2 weeks with a doubling within 13.5 days in vivo and in vitro cytokine stimulation of peripheral blood NK cells can result in expansion with a median of 16 (range 1130) population doublings.10

Figure 1 NK cells and other immune cells in the tumor microenvironment. NK cells of the CD56dim CD16+ phenotype secrete interferon- (IFN-), which increases the expression of MHC class I of tumor cells, enhancing the presentation of tumor antigens to T cells. Inhibitory checkpoint molecules expressed by NK cells can be blocked using specific monoclonal antibodies (ICIs). NK cells of the CD56bright CD16- phenotype recruit dendritic cells (DCs) to the tumor microenvironment (TME) and drive their maturation via chemokine ligands CCL5, XCL1 and FMS-related tyrosine kinase 3 ligand (FLT3L). DCs in turn stimulate NK and T cells via membrane-bound IL-15 (mbIL-15) and 41BBL secretion. Eventually, NK cells lyse tumor cells resulting in release of cancer antigens, which are then presented by DCs, to provoke specific T cell activation in relation with MHC class I molecules. The immunotherapeutic effect of NK cells includes the removal of immunosuppressive MDSCs.

NK cells are not only present in peripheral blood, lymph nodes, spleen, and bone marrow but they can also migrate to sites of inflammation in response to distinct chemoattractants. The majority of CD56dim subpopulation of the whole NK cells in peripheral blood (approximately 90%) exhibits high expression of the Fc receptor FcRIII (CD16), killer cell immunoglobulin-like receptors (KIRs) and perforin-mediated cytotoxicity whereas a minor population of CD56bright CD16- KIR- CD94/NKG2A+ (approximately 515%) of NK cells is primarily producing cytokines, including IFN- and TNF-1113 These two NK cell populations have been termed conventional NK cells in contrast to distinct tissue-resident NK cell populations localizing to liver, lymphoid tissue, bone, lung, kidney, gut and uterine tissue as well as distinct adaptive NK cell populations.14 However, CD56 and CD16 are not specific for NK cells and, furthermore, the heterogeneous tissue-resident populations show expression of adhesion molecules and CD69 and may represent an immature NK cell type. Adaptive NK cells are observed in connection with viral infections and exhibit memory cell-like properties. Overall, a wide diversity of receptor expressions of NK cells has been observed and, so far, the function of many of these subpopulations has not been fully characterized.

NK cells can eliminate target cells controlled by signals derived from activating (eg, NCRs or NKG2D) and inhibitory receptors (eg, KIRS or NKG2A).1517 Normal host cells are protected from NK cells attacks through inhibitory KIRs, that identify the self-MHC class I molecules.15 In particular, the germline-encoded NK receptors include the activating receptors NKG2D, DNAM-1, the natural killing receptors NKp30, NKp44, NKp46, and NKp80, the SLAM-family (Signaling Lymphocyte Activating Molecule) receptors for the elimination of hematopoietic tumor cells and the inhibitory KIRs.18 The activating signaling molecules promote tumor cell killing, cytokine production, immune cell activation, and proliferation and the NKpXX receptors, when engaged, all trigger alterations of the cellular calcium flux and NK cell-mediated killing and secretion of IFN- (Figure 1).

The interaction between KIRs and self-MHC molecules governs the maturation of NK cell, a process termed licensing.11,19,20 As alternative of MHC downregulation, cancer cells may be recognized by the overexpression of binding molecules for activating NK cell receptors. Ligands for the activating NKG2D receptor, such as MHC class I polypeptide-related sequence A (MICA), MICB and others are presented by cancer cells preferentially in response to cellular stress.21 A separate mechanism known as antibody-dependent cell cytotoxicity (ADCC) results in elimination of antibody-coated cell via the CD16 FcRIII receptor.22

NK cell-mediated lysis of target cells is mainly achieved through the release of the cytotoxic effector perforin and granzymes A and B but NK cells also produce a range of cytokines, both proinflammatory and immunosuppressive, such as IFN-, TNF- and IL10, respectively, as well as growth factors such as granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF) and IL-3 (Figure 1). CD56dim NK cells can produce very rapidly IFN- within 2 to 4 hours after triggering through NKp46 and NKp30 activating receptors (ARs).12,13 NK cellderived cytokine production impacts dendritic cells, macrophages and neutrophils and empower NK cells to regulate subsequent antigen-specific T and B cell responses. Activated NK cells lose CD16 (FcRIII) and CD62 ligand through the disintegrin and metalloprotease 17 (ADAM17), and inhibition of this protease enhances CD16-mediated NK cell function. Cytokine stimulation also downregulates CD16 and upregulates CD56 expression. Moreover, certain cytokines can greatly enhance the cytotoxicity and cytokine production of the CD162 CD56bright and CD161 CD56dim NK cell subsets, respectively.23,24

In cancer patients, NK cells target cells low/deficient of MHC-class I or bearing altered-self stress-inducible proteins.17,25 Besides tumor cell killing through release of perforin and granzyme and secretion of immunoregulatory mediators such as nitric oxide (NO) effects cell death mediated by TNF-family members such as Fas-L or TRAIL. The degree of tumor infiltration of NK cells seems to have prognostic value in gastric carcinoma, colorectal carcinoma and lung carcinomas, thus indicating a protective role of the NK cell infiltrate.26,27 NK cell infiltration of tumors depends on their expression of heparinase.28 NK cells may further attract T cells to the tumor region and elevate inflammatory responses through secretion of cytokines and chemokines.29 Furthermore, NK cells have been suggested to suppress metastasis through elimination of circulating tumor cells (CTCs).30

NK cells seem well suited for anticancer immunotherapy and cells for clinical administration can be isolated from peripheral or umbilical cord blood. Peripheral blood NK cells are prepared by leukapheresis and further enriched by density gradient centrifugation (Figure 2). Subsequently, the combination of T cell depletion with CD56 cell enrichment yields highly purified NK cell populations.31 NK cells gained from peripheral blood of healthy persons are typically in a resting state and can be activated by exposure to IL-2. However, supplementation with IL-2 and infusion to cancer patients has resulted in severe side effects, such as vascular leak syndrome and liver toxicity.32 Studies with native autologous NK cells have yielded disappointing results. The most efficient NK cell expansion was observed with K562 NK target cells co-expressing membrane-bound IL-15 (mbIL-15) and 41BBL.31 This technique yields enough NK to provide cells for at least four infusions at 50 million cells/per kg from one leukapheresis product observing GMP conditions.31 However, many mechanisms mediate NK cell suppression in the tumor microenvironment (TME), several of which also impair T cell responses.33,34 In case of NK cells, NKG2D ligand release can occur by shedding and these soluble ligands prevent NK cell-tumor cell interaction and the cytotoxic response.35,36

Figure 2 Isolation, activation and propagation of allogeneic NK cells. Peripheral blood mononuclear cells (PBMCs) are prepared from healthy donors by leukapheresis. PBMC depletion of CD3+ T cells, prevents GvHD after infusion and further purification is achieved by positive CD56+ cell selection. These cell preparations are infused or activated with IL-2 or a mixture of IL-12, IL-15 and IL-18. Another method for NK cell stimulation involves ex vivo coculture with the K562 cell line expressing membrane-bound IL-15 (mbIL-15) and 41BBL that is irradiated to abolish expansion. Umbilical cord blood NK cells can be used similar to peripheral blood NK cells or enriched for CD34+ hematopoietic progenitors, followed by differentiation to NK cells. NK cells can be gained from induced pluripotent stem cells (iPSCs) via successive hematopoietic and NK cell differentiation, followed by stimulation with cells expressing mbIL-21. Before infusion of allogeneic NK cells, patients receive lymphodepleting chemotherapy to facilitate temporary engraftment of the infused NK cells.

In summary, NK cells are functional in tumor surveillance and can be manipulated by artificial activation techniques to present a highly effective anticancer tool against hematopoietic malignancies and, dependent on successful further rearming and mobilization, against solid tumors in the future.

The lungs are frequently challenged by pathogens, environmental damages and tumors and contain a large population of innate immune cells.37,38 Involvement of NK cells in lung diseases, such as cancer, chronic obstructive pulmonary disease (COPD), asthma and infections, has been amply reported.39 Chronic inflammation drives the irreversible obstruction of the lung function in COPD and local NK cells show hyperresponsiveness in COPD and kill autologous lung CD326+ epithelial cells.40 Therefore, targeting NK cells may represent a novel strategy for treating COPD. Furthermore, NK cells from cigarette smoke-exposed mice produce higher levels of IFN- upon stimulation with cytokines or toll-like receptor (TLR) ligands.41

Lung NK cells account for approximately 1020% of local lymphocytes and have migrated to the lungs from bone marrow.42 These cells exhibit the phenotype of the CD56dim CD16+ subset and are located in the parenchyma.43 Lung NK cells show major differences in phenotype and function to those from other tissues and, for example, KIR-positive NK cells and differentiated CD57+ NKG2A cells are found in higher numbers in the lungs compared to matched peripheral blood.37,38 In vivo, human lung NK cells respond poorly to activation by target cells in comparison to peripheral blood NK cells, most likely due to suppressive effects of alveolar macrophages and soluble factors in the fluid of the lower respiratory tract.44 The presence of hypofunctional NK cells seems to regulate the pulmonary homeostasis in the presence of constantly irritation by environmental and autologous antigens.

Unlike other tissues, the lung NK cell diversity and its acquisition have been very little studied, especially regarding the resident lung populations. Although the majority of lung NK cells are of a non-tissue-resident phenotype, a small CD56bright CD49a+ lung NK cell subset has been found.45 NK cell diversity occurs for the main resident population within the lung, namely CD49a+CD56bright CD16 NK cells that can be split into four different resident subpopulations according to the residency markers CD69 and CD103.47 The CD69+CD103+ subset is the most important as compared to single positive or double negative subsets. The respective significance of these subsets in terms of ontogeny, differentiation, or functionality remains to be characterized.

The CD16 NK cells in the human lung comprises a heterogeneous cell population and the CD69+CD49a+CD103 and CD69+CD49a+CD103+ tissue-resident NK cells are clearly distinct from other NK cell subsets in the lung and other tissues, whereas CD69spCD16 NK cells (lacking expression of CD49a and/or CD103) largely represent conventional CD69CD16 NK cells.47 Furthermore, lung tissue-resident NK cells are functionally competent and constitute a first line of defense in the human lung. Protein and gene expression signatures of CD16 NK cell subsets correlated with distinct patterns of expression of CD69, CD49a, and CD103 and corroborated the CD69+CD49a+CD103 and CD69+CD49a+CD103+ NK cells as tissue-resident NK cells.48 In contrast, CD69spCD16 NK cells are more similar to CD69CD16 NK cells and showed lower expression of genes associated with tissue-residency.

On the course of NK cell differentiation less differentiated NK cells are hypofunctional but respond stronger to cytokine stimulation and more differentiated NK cells exert more potent ADCC-dependent cell killing.46,49 The early activation antigen CD69 is expressed on a wide range of tissue-resident lymphocytes, including T cells and NK cells, and promotes retention of the cells in the tissue.38,50 Highly differentiated and hypofunctional CD69+ CD56dim CD161+ NK cells constitute the dominant NK cell population in the human lung. In summary, these results indicate that the human lung is mainly populated by NK cells migrating between lung and blood, rather than by CD69-positive tissue-resident cells. The mechanisms controlling this distribution of the lymphocyte populations is not known but may comprise changes in the homing of NK cells, increased apoptosis of NK cells and increased expansion or recruitment of tissue-resident T cells.

Although the incidence of lung cancer is declining, the survival rates remain poor due to a lack of early detection and only recent progress in targeted cancer therapies that are still only feasible for a limited subpopulation of patients.51,52 The host of immune cells involved in lung cancer include CD4+ and CD8+ T lymphocytes, neutrophils, monocytes, macrophages, innate lymphoid cells (ILCs), dendritic cells and NK cells. In lung cancer patients, peripheral NK cell cytotoxicity and INF- production was reported to be reduced.5356 Especially, a lower cytotoxic activity in NK cells was observed in smokers due to the suppression of the induction of IL-15 and IL-15-mediated NK cell functions in human PBMCs.57 Furthermore, the granzyme B release by NK cells from lung cancer tissue is lower compared to adjacent normal tissue.58 Additionally, peripheral NK cells of NSCLC patients are present in lower cell numbers and display a distinctive receptor expression with downregulation of NKp30, NKp80, CD16, DNAM1, KIR2DL1, and KIR2DL2, but upregulation of NKp44, NKG2A, CD69, and HLA-DR. Furthermore, low levels of IFN- and CD107a result in impaired cytotoxicity and promotion of tumor growth.54,59,60 The CD56bright CD16-NK cell subset is highly enriched in the tumor infiltrate and show activation markers, including NKp44, CD69, and HLA-DR.5961 However, the release of soluble factors by NSCLC tumor cells inhibit the activity of granzyme B and perforin and the induction of IFN- in intratumoral NK cells and suggest a local inhibition of NK cells by the NSCLC TME.62 T cell immune checkpoint molecules programmed cell death 1 (PD-1), cytotoxic T lymphocyte antigen 4 (CTLA4), lymphocyte activation gene 3 protein (LAG3) and TIM3 are expressed by subpopulations of NK cells and might reduce NK antitumor responses. In solid tumors, vascular supply may be ineffective causing hypoxia and low nutrient levels in the TME that may impair NK cell metabolism and antitumor cytotoxicity as demonstrated in lung experimental animal models.63,64 Additionally, the CD56bright CD16- NK cells enhance protumor neoangiogenesis through secretion of VEGF, placental growth factor and IL-8/CXCL8.65

Small cell lung cancer (SCLC) is a pulmonary neuroendocrine cancer linked to smoking that has a dismal prognosis and invariably develops resistance to chemotherapy within a short time.66 Despite a high tumor mutational burden, immune checkpoint inhibitors show minor prolongation of survival in SCLC patients.66,67 In particular, Nivolumab (anti-PD1 antibody) was approved for third-line treatment and the combination of atezolizumab (anti-PDL1 antibody) with carboplatin and etoposide was approved for first-line treatment of disseminated SCLC, resulting in minor survival gains.68,69 NK cells are critical in suppressing lung tumor growth and while low MHC expression would make SCLC resistant to adaptive immunity, this should make SCLCs susceptible to NK cell killing.64,70 In comparison to the peripheral blood NK cells of healthy individuals, the NK cells of SCLC patients are present in equal cell counts but exhibit lower cytotoxic activity, downregulation of NKp46 and perforin expression.55 Lack of effective NK surveillance seems to contribute to SCLC progress, primarily through the reduction of NK-activating ligands (NKG2DL). SCLC primary tumors possess very low levels of NKG2DL mRNA and SCLC lines largely fail to express NKG2DL at the protein level.66,71 Accordingly, restoring NKG2DL in experimental models suppressed tumor growth and metastasis in a NK cell-dependent manner. Furthermore, histone deacetylase (HDAC) inhibitors induced NKG2DL re-expression and resulted in tumor suppression by NK and T cells. Actually, SCLC and neuroblastoma are the two tumor types with lowest NKG2DL-expression. In conclusion, epigenetic silencing of NKG2DL results in a defect of NK cell activation and immune escape of SCLC and neuroblastoma. Poor immune infiltrates in SCLC tumors combined with reduced NK and T cell recognition of the tumor cells seem to contribute to immune resistance of SCLCs.72

A majority of NSCLC patients do not benefit from the current IC-directed immunotherapy. CD56dim CD16+ NK cells comprise the majority of NK cells in human lungs and express KIRs and a more differentiated phenotype compared with NK cells in the peripheral blood.38,73 However, human lung NK cells were hyporesponsive toward target cell stimulation, irrespective of priming with IFN-. NK cells are activated by MICA and MICB expressed by stressed tumor cells and are recognized by NK cell receptors NKG2D.74 Preclinical studies show that NKG2A or TIGIT blockade enhances antitumor immunity mediated by NK cells.2 However, the poor infiltration of NK cells into solid tumors, alterations in activating/inhibitory signals and adverse TME conditions decrease the NK-mediated killing. NK cells can be inactivated by different cells such as Tregs and MDSCs but also by soluble mediators such as adenosine.75,76 Adenosine represents one of the most potent immunosuppressive factors in solid tumors that is produced in the tumor stroma by degradation of extracellular ATP.7779 ATP and ADP are degraded by membrane-expressed ectonucleotidases such as CD39 and enhance the influx and the suppressive capacity of Tregs and MDSCs in solid tumors. NK cells are strongly involved in eliminating circulating tumor cells (CTCs), but their activity can be inhibited by soluble factors, such as TGF- derived from M2 macrophages.80,81 One approach uses cytokines to selectively boost both the number as well as the efficacy of anti-tumor functions of peripheral NK cells.82 The gene signature of NK cell dysfunction in human NSCLC revealed an altered migratory behavior with downregulation of the sphingosine-1-phosphate receptor 1 (S1PR1) and CX3C chemokine receptor 1 (CX3CR1).83 Additionally, the expression of the immune inhibitory molecules CTLA-4 and killer cell lectin like receptor (KLRC1) were elevated in intratumoral NK cells and CTLA-4 blockade could partially restore the impaired MHC class II expression on dendritic cell (DC). In summary, the intratumoral NK dysfunction can be attributed to direct crosstalk between tumor and NK cells, activated platelets and soluble factors, such as TGF-, prostaglandin E2, indoleamine-2,3-dioxygenase, adenosine and IL-10.19,26,54,83 In addition, a specific migratory signature could explain the exclusion of NK cells from the tumor interior. NK cells in NSCLC distribute to the intratumoral fibrous septa and to the borders between tumor cells and surrounding stroma.54,59 It has been suggested that a barrier of extracellular matrix proteins may be responsible for the restriction of NK cells primarily to the tumor stroma, such preventing direct NK celltumor cell interactions.84,85 In contradiction, ultrastructural investigations demonstrated NK cells are rather flexible and capable of extravasation and intratumoral migration.59 CD56bright CD162+ NK cells express CCR5 that is known to mediate the chemoattraction of specific leukocyte subtypes and explain their accumulation in tumor tissues.13 Infiltration of the tumors by NK cells was reported to be linked with a favorable prognosis in lung cancer.26,86 However, Platonova et al reported that NK cell infiltration lacks any correlation with clinical outcomes in NSCLC.47,54 The poor prognostic significance of NK cells in NSCLC seems to be associated with the intratumoral NK cell dysfunction in patients with intermediate or advanced-stage tumors.

It would be of great importance to target chemokine receptors on NK cells to enable them to enter tumor tissues. NK cells acquire inhibitory functions within the TME, the reversion of which will enable NK cells to activate other immune cells and exert antitumor cytotoxic functions.87 In addition, several clinical trials based on NK cell checkpoints are ongoing, targeting KIR, TIGIT, lymphocyte-activation gene 3, TIM3 and KLRC1.88 NK cell dysfunction favors tumor progress and restoring NK cell functions would represent an important potential strategy to inhibit lung cancer. These approaches include the activation of NK cells by exposing to interleukins such as IL-2, IL-12, IL-15, IL-18, the blockade of inhibitory receptors of NK cells by targeting NKG2A, KIR2DL1 and KIR2DL2 as well as the enhancement of NK cell glycolysis by inhibition of fructose-1,6-bisphosphatase 1 and altering the immunosuppressive TME by neutralization of TGF-.37,53 Pilot clinical trials of NK cell-based therapies such as administration of cytokines, NK-92 cell lines and allogenic NK cell immunotherapy showed promising outcomes on the lung cancer survival with less adverse effects. However, due to the lack of larger clinical trials, the NK cell targeting strategy has not been approved for lung cancer treatment so far.

Most of studies regarding NK cell-based immunotherapy have been performed in hematologic malignancies. However, there are increasingly data available that show that NK cells can selectively recognize and kill cancer stem cells in solid tumors.89 Furthermore, Kim et al showed the essential role of NK cells in prevention of lung metastasis.90 Additionally, Zhang et al studied the efficacy of adaptive transfer of NK and cytotoxic T-lymphocytes mixed effector cells in NSCLC patients.91 A prolonged overall survival was detectable in patients after administration of NK cell-based immunotherapy. In a trial of Lin et al, the clinical outcomes of cryosurgery combined with allogenic NK cell immunotherapy for the treatment of advanced NSCLC were improved with elevated immune functions and quality of life.92

The efficacy of NK cell-based adoptive immunotherapy was also investigated in SCLC patients. Ding et al studied the efficacy and safety of cellular immunotherapy with autologous NK, T cells and cytokine-induced killer cells as maintenance therapy for 29 SCLC patients and demonstrated an increased survival of the patients.93 Importantly, lung cancer-infiltrating NK cells can mainly function as producers of relevant cytokines, either beneficial or detrimental for the antitumor immune response, and activation can transform CD56bright CD162+ KIR2+ NK cells into CD56dim CD161+ KIR1+ NK cells with higher cytotoxic activity.94 The switch from a CD56bright phenotype to a CD56dim NK cell signature can take place in lymph nodes during inflammation and these cells circulate into peripheral blood as KIR+CD16+ NK cells with low cytotoxic ability. However, the secondary lymphoid organ (SLO) NK cells acquire cytotoxic activity upon stimulation with IL-2. Malignant NSCLC tumor areas show high presence of Tregs and minor NK cell infiltration, whereas non-malignant regions were oppositely populated, containing NK cells with marked cytotoxicity ex vivo.95 IL-2 activation of PMBCs exhibit increased cytotoxic activity against primary lung cancer cells, that is further elevated by IL-12 treatment.96 The adoptive transfer of NK cells is a therapeutic strategy currently being investigated in various cancer types. For example, Krause et al treated a NSCLC patient and 11 colorectal cancer patients with autologous transfer of NK cells activated ex vivo by a peptide derived from heat shock protein 70 (Hsp70) plus low-dose IL-2.97 The NK cell reinfusion revealed minor adverse effects and yielded promising immunological alterations.

Adaptive-like CD56dim CD16+ NK cells that were found in studies in mice and humans in peripheral blood have a distinctive phenotypic and functional profile compared to conventional NK cells.31,98 These cells have a high target cell responsiveness, as well as a longer life time and a recall potential comparable to that of memory T cells.99 Whereas adoptive NK cell transfer showed promising activities in the treatment of hematological malignancies, elimination of solid tumor cells failed due to insufficient migration and tumor infiltration.100 Furthermore, a CD49a+ KIR+ NKG2C+ CD56bright CD16 adaptive NK cell population with features of residency exists in human lung, that is distinct from adaptive-like CD56dim CD16+ peripheral blood NK cells.43 NK cells with an adaptive-like CD49a+ NK cell expansion in the lung proved to be hyperresponsive toward cancer cells. Despite their in vivo priming, the presence of adaptive-like CD49a+ NK cells in the lung did not correlate with any clinical parameters.

At the time of diagnosis, the majority (80%) of lung cancer patients present with locally advanced or metastatic disease that continues to progress despite chemotherapy.101 Lung cancer remains the leading cause of cancer death worldwide despite the responses found for immune checkpoint inhibitors (ICIs), including programmed death receptor-1 (PD1) or PD ligand 1 (PDL1)-blockade therapy.102 These ICIs has achieved marked tumor regression in some patients with advanced PD1/PDL1-positive lung cancer; however, lasting responses were limited to a 15% subpopulation of patients.103 IFN-, released by cytotoxic NK and T cells, is a critical enhancer of PDL1 expression on tumors and a predictor of response to immunotherapies.104 The high failure rate of immunotherapy seems to be a consequence of low tumor PDL1 expression and the action of further immunosuppressive mechanisms in the TME.105

NK cells expanded from induced-pluripotent stem cells (iPSCs) increased PDL1 expression of tumor cell lines, sensitized non-responding tumors from patients with lung cancer to PD1-targeted immunotherapy and killed PDL1- patient tumors (Figure 2).102 In contrast, native NK cells, that are susceptible to immunosuppression in the TME, had no effect on tumor PDL1 expression. Accordingly, only combined treatment of expanded NK cells and PD1-directed inhibitors resulted in synergistic tumor cell kill of initially non-responding patient tumors. A randomized control trial in patients with PDL1+ NSCLC found that the combination treatment of NK cells with the PD1 inhibitor pembrolizumab was well-tolerated and improved overall and progression-free survival in patients compared single agent pembrolizumab treatment.106 Importantly, during this clinical study no adverse events associated with the administration of NK cells were detected.

Early trials of autologous NK cell therapy from leukapheresis have demonstrated potency against several metastatic cancers but patients developed vascular leak syndrome due to a high level of IL-2.32,107 In contrast, other studies reported that these autologous NK cells failed to demonstrate clinical responses or efficacy at large.108,109 Adoptive transfer of ex vivo IL-2 activated NK cells showing better outcomes than the systemic administration of IL-2.107,110 The development of novel NK cell-mediated immunotherapies presumes a rich source of suitable NK cells for adoptive transfer and an enhancement of the NK cell cytotoxicity and durability in vivo. Potential sources comprise haploidentical NK cells, umbilical cord blood NK cells, stem cell-derived NK cells, permanent NK cell lines, adaptive NK cells, cytokine-induced memory-like NK cells and chimeric antigen receptor (CAR) NK cells (Figure 2). Augmentation of the cytotoxicity and persistence of NK cells under clinical investigation is promoted by cytokine-based agents, NK cell engager molecules and ICIs.111,112 Despite some successes, most patients failed to respond to unmodified NK cell-based immunotherapy.113

Clonal NK cell lines, such as NK-92, KHYG-1 and YT cells, are an alternative source of allogeneic NK cells, and the NK-92 cell line has been extensively tested in clinical trials.114116 NK-92 cells are easily expanded with doubling times between 24 and 36 hours.115 NK-92 has received FDA approval for trials in patients with solid tumors.116 These cells are genetically unstable, which requires them to be irradiated prior to infusion. Irradiated NK-92 cells have been observed to kill tumor cells in patients with cancer, although irradiation limits the in vivo persistence of these cells to a maximum of 48 hours.117 The results are still short of a significant clinical benefit.118 An NK-92- derived product (haNK) has been engineered to express a high-affinity variant of CD16 as well as endogenous IL-2 in order to enhance effector function (Figure 2).119121 For example, Dinutuximab is a product of human-mouse chimeric mAb (ch14.18 mAb), which has demonstrated high efficacy against GD2-positive neuroblastoma cells in vitro and melanoma cells in vivo.122 In MHC-I expressing tumor cells, the effector functions of autologous NK cells are often inhibited by KIR that can be blocked with the help of anti-KIR (IPH2101).123 Stem cell-derived NK cell products from multiple sources are currently being tested clinically, including those originating from umbilical cord blood stem cells or iPSCs.124,125 NK cells account for ~515% of all lymphocytes in peripheral blood, whereas they constitute up to 30% of the lymphocytes in umbilical cord blood.126 iPSC-derived NK cells were triple gene- modified to express cleavage-resistant CD16, a chimeric antigen receptor (CAR) targeting CD19 and a membrane-bound IL-15 receptor signaling complex in order to promote their persistence.127 Thus, investigations to provide highly active modified NK cells in numbers sufficient for clinical application are actively pursued.

CAR T cells are derived from autologous T cells and genetically engineered to express an antibody single-chain variable fragment (scFv) targeting a tumor-associated antigen.128 CAR T cell therapies achieved objective response rates of >80% in patients with acute lymphocytic leukemia (ALL) and B cell non-Hodgkin lymphoma.129131 However, the drawbacks of CAR T therapy include severe adverse events such as GvHD,cytokine-release syndrome and neurological toxicities, besides inefficiencies of T cell isolation, modification and expansion as well as exorbitant costs.132 CAR NK therapy is expected to circumvent some of these problems, including the high toxicities. Primary NK cells are not ideal sources for the generation of CAR cell products, due to difficulties in cell isolation, transduction and expansion. However, NK cell expansion could be greatly improved by involvement of a K562 leukemia cell line feeder modified to express membrane-bound IL-15 (mbIL-15; Figure 2).133 Denman et al improved this method adding membrane-bound 41BBL to the K562 cell line resulting in a high expansion of NK cells within a short time.134,135 Nevertheless, current clinical trials of CAR NK cells rely mainly on processing of stem cell-derived or progenitor NK cells.136 Genetic engineering of NK cells has been performed by viral transduction or electroporation of mRNA.3 Many clinical trials of CAR NK-92 cells are ongoing, but the requirement for irradiation and resulting short persistence are limitations to the clinical efficacy of these products. NK92-CD16 cells preferentially killed tyrosine kinase inhibitor (TKI)-resistant NSCLC cells when compared with their parental NSCLC cells.137 Moreover, NK92-CD16 cell-induced cytotoxicity against TKI-resistant NSCLC cells was increased in the presence of cetuximab, an EGFR-targeting monoclonal antibody. A number of Phase I trials of CAR NK cells from various sources, including autologous peripheral blood NK cells, umbilical cord blood NK cells, NK-92 cells and iPSCs were designed to target diverse cancers, such as ALL, B cell malignancies, NSCLC, ovarian cancer or glioblastoma, and are currently active.

CAR NK cells derived from iPSCs, such as the triple-gene-modified constructions are described as a promising alternative. For example, a tri-specific killer engager (TriKE) consists of two scFvs, one targeting CD16 on NK cells and the other targeting CD33 on AML cells, linked by an IL-15 domain that promotes NK cell survival and proliferation.138 Controlled clinical trials with larger patient cohorts are required to validate these early results. Immunosuppressive factors of the TME, such as low glucose, hypoxia and MDSCs, Treg cells and tumor associated macrophages (TAMs) still suppress the antitumor functions of CAR-NK cells. Low efficiency of CAR-transduction, limited cell expansion and the scarcity of suitable targets impede the use of CAR-NK therapy despite of reports of therapeutic efficacy and safety.139

The cytokine gene transfer approaches, including interleukins and stem cell factor (SCF), have been shown to induce NK cell proliferation and increases survival capacity in vivo.140 The use of primary CAR-NK and CAR-NK lines in hematological tumors showed high specificity and cytotoxicity toward the target cells.141,142 So far, only a few clinical trial studies of CAR-NK have been registered on ClinicalTrials.gov.143 The combination of blocking ICIs on CAR-NK cells can lead to a highly efficient cancer-redirected cytotoxic activity.144,145 However, hematological cancers are responsible for only 6% of all cancer deaths and solid tumor are much more difficult to target by NK/CAR NK-based immunotherapy.146

Both the unmodified and the engineered forms of NK cell treatment are showing promise in pilot clinical trials in patients with cancer.147 This kind of immunotherapy seems to combine efficacy, safety, and relative ease of effector cell supply. The lung is populated by NK cells at a specific differentiation stage releasing cytokines but exhibiting low cytotoxicity. Poor tumor infiltration, immunosuppressive factors and cell types as well as hypoxic conditions in the TME limit the activity of NK cells. Therefore, larger numbers of activated, cytotoxic competent and armed NK cells will be required for successful therapy.

We wish to thank B. Rath for help in the preparation of the manuscript and T. Hohenheim for enduring endorsement.

The authors report no conflicts of interest in this work.

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Impact of NK cell-based therapeutics for Lung Cancer Therapy | BTT - Dove Medical Press

Bone Marrow Stem Cells Comments Off on Impact of NK cell-based therapeutics for Lung Cancer Therapy | BTT – Dove Medical Press | July 7th, 2021

Our cells have abilities that go far beyond the fastest, smartest computer. They generate mechanical forces to propel themselves around the body and sense their local surroundings through a myriad of channels, constantly recalibrating their actions.

The idea of using cells as medicine emerged with bone marrow transplants, and then CAR-T therapy for blood cancers. Now, scientists are beginning to engineer much more complex living therapeutics by tapping into the innate capabilities of living cells to treat a growing list of diseases.

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That includes solid tumors like cancers of the brain, breast, lung, or prostate, and also inflammatory diseases like diabetes, Crohns, and multiple sclerosis. One day, this work may extend to regenerating tissues outside or even inside the body.

Taking a page from computer engineers, biologists are trying their hands at programming cells by building DNA circuits to guide their protein-making machinery and behavior.

We need cells with GPS that never make mistakes in where they need to go, and with sensors that give them real-time information before they deliver their payload, said Hana El-Samad, PhD, a professor of biochemistry and biophysics. Maybe they kill a little bit and then deliver a therapeutic payload that cleans up. And the next program over encourages the rejuvenation of healthy cells.

These engineered cell therapies would be a huge leap from traditional therapies, like small molecules and biologics, which can only be controlled through dose, or combination, or by knowing the time it takes for the body to get rid of it.

If you put in drugs, you can block things and push things one way or the other, but you can't read and monitor whats going on, said Wendell Lim, PhD, a professor of cellular and molecular pharmacology who directs the Cell Design Institute at UCSF. A living cell can get into the disease ecosystem and sense what's going on, and then actually try to restore that ecosystem.

Like people, cells live in communities and share duties. They even take on new identities when the need arises, operating through unseen forces that biologists term, self-organizing.

We need cells with GPS that never make mistakes in where they need to go, and with sensors that give them real-time information before they deliver their payload.

Hana El-Samad, PhD

Some living cell therapies could be controlled even after they enter the body.

Lim and others say it is possible to begin adapting cells into therapy, even when so much has yet to be learned about human biology, because cells already know so much.

Their built-in power includes dormant embryonic abilities, so a genetic nudge in the right place could enable a cell to assume a new function, even something it has never done before.

When a cell, a building block thats 10 microns in diameter can do that, and you have 10 trillion of them in your body, its a whole new ballgame, said Zev Gartner, PhD, a professor of pharmaceutical chemistry who studies how tissues form. Were not talking about engineering in the same way that somebody working at Ford or Intel or Apple or anywhere else thinks about engineering. Its a whole new way of thinking about engineering and construction.

For several years now, synthetic biologists have been building rudimentary feedback circuits in model organisms like yeast by inserting engineered DNA programs. Recently, Lim and El-Samad put these circuits into mice to see if they could tamp down the excess inflammation from traumatic brain injury.

They demonstrated that engineered T-cells could get into the sites of injury in the brain and perform an immune-modulating function. But its just a prototype of what synthetic circuits could do.

You can imagine all kinds of scenarios of therapies that dont cause any side effects, and do not have any collateral damage, said El-Samad.

UCSF researchers are building ever more complex circuits to move cells around the body and sense their surroundings. They hope to load them with DNA programs that trigger the cells protein-making machinery to do things like remove cancerous cells, then repair the damage caused by the tumors haphazard growth.

Or they could make cells that send signals to finetune the immune system when it overreacts to a threat or mistakenly attacks healthy cells. Or build new tissue and organs from our bodys own cells to repair damage associated with trauma, disease, or aging.

The fact that biological systems and cellular systems can self-organize is a huge part of biology, and thats something were starting to program, Lim said. Then we can make cells that do the functions that we want. We aspire to not only have immune cells be better at killing and detecting cancer but also to suppress the immune system for autoimmunity and inflammation or go to the brain to fight degeneration.

These UCSF scientists are on their way to engineering cell-based solutions to different diseases.

Tejal Desai, PhD, a professor and chair of the Department of Bioengineering and Therapeutic Sciences, is employing nanotechnology to create tiny depots where cells that have been engineered to treat Type 1 diabetes or cancer can refuel with oxygen and nutrients.

Having growth factors or other factors that keep them chugging along is very helpful, she said. Certain cytokines help specific immune cells proliferate in the body. We can design synthetic particles that present cytokines and have a signal that says, Come over to me. Basically, a homing signal.

Ophir Klein, MD, PhD, a professor of orofacial sciences and pediatrics, employs stem cell biology to research treatments for birth defects and conditions like inflammatory bowel disease. He is working with Lim and Gartner to create circuits that induce cells to grow in new ways, for example to repair the damage to intestines in Crohns disease.

Cells and tissues are able to do things that historically we thought they were incapable of doing, Klein said. We dont assume that the way things happen or dont happen is the best way that they can happen, and were trying to figure out if there are even better ways.

Faranak Fattahi, PhD, a Sandler Faculty Fellow, is developing cell replacement therapy for damaged or missing enteric neurons, which regulate the muscles that move food through the GI tract. She generated these gut neurons using iPS cell technology.

What we want to do in the lab is see if we can figure out how these nerves are misbehaving and reverse it before transplanting them inside the tissue, she said. Now, she is working with Lim to refine the cells, so they integrate into tissues more efficiently without being killed off by the immune system and work better in reversing the disease.

Matthias Hebrok, PhD, a professor in the Diabetes Center, has created pancreatic islets, a complex cellular ecosystem containing insulin-producing beta cells, glucagon-producing alpha cells and delta cells.

Now, he is working on how to make islet transplants that dont trigger the immune system, so diabetes patients can receive them without immune-suppressing drugs.

We might be able to generate stem-cell derived organs that the recipients immune system will either recognize as self or not react to in a way that would disrupt their function.

In health, the community of cells in these islets perform the everyday miracle of keeping your blood sugar on an even keel, regardless of what you ate or drank, or how little or how much you exercised or slept.

To me, at least, thats the most remarkable thing about our cells, Gartner said. All of this stuff just happens on its own.

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Beyond CAR-T: New Frontiers in Living Cell Therapies - UCSF News Services

Bone Marrow Stem Cells Comments Off on Beyond CAR-T: New Frontiers in Living Cell Therapies – UCSF News Services | July 7th, 2021

Firstly, two news items on glioblastoma that will be of particular interest to scientists at our Research Centre at Queen Mary, University of London. This brain tumour type is the most aggressive and most common primary high-grade tumour diagnosed in adults.

We begin with some fascinating research into a new stage of the stem cell life cycle could be the key to unlocking new methods of brain cancer treatment. Following brain stem cell analysis, through single-cell RNA sequencing, data mapped out a circular pattern that has been identified as all of the different phases of the cell cycle. A new cell cycle classifier tool then took a closer, high-resolution look at what's happening within the growth cycles of stem cells and identified genes that can be used to track progress through this cell cycle. When the research team analysed cell data for Gliomas, they found the tumour cells were often either in the Neural G0 or G1 growth state and that as the tumours became more aggressive, fewer and fewer cells remained in the resting Neural G0 state. They correlated this data with the prognosis for patients with Glioblastoma and found those with higher Neural G0 levels in tumour cells had less aggressive tumours. So, if more cells could be pushed into this quiescent, or sleepy, state tumours would become less aggressive. Current cancer drug treatments focus on killing cancer cells. However, when the cancer cells are killed, they release cell debris into the surrounding area of the tumour, which can cause the remaining cells to become more resistant to drugs. If, instead of killing cells, we put them to sleep could that potentially be a better way forward?

For the first time, scientists have discovered stem cells of the hematopoietic system in glioblastomas. These hematopoietic stem cells promote division of the cancer cells and at the same time suppress the immune response against the tumour so Glioblastomas. In tissue samples of 217 Glioblastomas, 86 WHO grade II and III Astrocytomas, and 17 samples from healthy brain tissue, researchers used computer-assisted transcription analysis to draw up profiles of the cellular composition. The tissue samples were taken directly from the post-surgery, resection margins - where remaining tumour cells and immune cells meet. The team were able to distinguish between signals from 43 cell types, including 26 different types of immune cells. To their great surprise, the researchers discovered hematopoietic stem and precursor cells in all the malignant tumour samples, while this cell type was not found in healthy tissue samples. An even more surprising observation was that these blood stem cells seem to have fatal characteristics: They suppress the immune system and at the same time stimulate tumour growth. When the researchers cultured the tumour-associated blood stem cells in the same petri dish as Glioblastoma cells, cancer cell division increased. At the same time, the cells produced large amounts of the PD-L1 molecule, known as an "immune brake", on their surface.

On diagnosis of an Ependymoma an adult is often treated with surgery followed by radiation. When a tumour comes back, there had been no standard treatment options. Recently, thats changed, thanks to results from the first prospective clinical trial for adults with Ependymoma, which showed the benefits of a combination regimen including a targeted drug and chemotherapy.

Also of relevance to our Research Centre at QMUL, a study may have identified the cell of origin of Medulloblastoma. Using organoids to simulate tumour tissue in 3D an approach also used by researchers at QMUL - this organoid model has enabled researchers to identify the type of cell that can develop into Medulloblastoma. These cells express Notch1/S100b, and play a key role in onset, progression and prognosis.

Research has been looking at how Medulloblastoma travels to other sites within the central nervous system and has shown that an enzyme called GABA transaminase, abbreviated as ABAT, aids metastases in surviving the hostile environment around the brain and spinal cord and in resisting treatment. These findings may provide clues to new strategies for targeting lethal Medulloblastoma metastases.

You can register to join an online lecture on the molecular analysis of paediatric Medulloblastoma and vulnerabilities, the development of models that recapitulate the patients diseases and how models allow to identify new therapies using a pre-clinical pipeline. It is on July 13th.

From the 12 15 of August you can watch The Masters Live World Course in Brain and Spine Tumour Surgery this event wont be streamed or saved on social media and registration is free.

Still focussing on neuro surgery this link takes you to a Neurosurgeon's guide to Cognitive Dysfunction in Adult Glioma

Grounds for optimism to end with as a prominent clinician/scientist believes Glioblastoma outcomes could change for the better soon. Frederick F. Lang Jr, MD, chair of neurosurgery at The University of Texas MD Anderson Cancer Centre, and a co-leader of the institutions Glioblastoma Moon Shot programme says I am optimistic that we are going to see changes in the survival as we start to [better] understand the groups of people we're treating, and as we separate out the tumours more precisely and classify them better. Then, as we understand the biology of [the disease] better and better, we're going to see changes in the near future terms of survival. The University of Texas MD Anderson Cancer Centre is pursuing several novel approaches, including viro-immunotherapy and genetically engineered natural killer cells to treat patients with GBM, while also conducting tumour analysis to better comprehend the disease.

Whether to find out more about the Glioblastoma tumour microenvironment work or research into Medulloblastoma carried out at our Queen Mary University of London (QMUL) centre, the techniques at the forefront of tumour neurosurgery being employed by Consultant Neurosurgeon Kevin ONeill at our Imperial College, London Centre or the work into Meningioma and Acoustic Neuroma ( Thursday was Acoustic Neuroma Awareness Day) that Professor Oliver Hanemann focuses on at our University of Plymouth Centre, it is always worth checking our Research News pages and for an overview of our research strategy check out Brain Tumour Research our research strategy.

Finally, a request for you all to support our #StopTheDevastation campaign click through, find out more, get involved and say #NoMore to brain tumours.

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Sleeper cells, cells of origin and hematopoietic stem cells - Brain Tumour Research

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