Category Archives: Adult Stem Cells

Little Skates Could Hold the Key to Cartilage Therapy in Humans – Technology Networks

Nearly a quarter of Americans suffer from arthritis, most commonly due to the wear and tear of the cartilage that protects the joints. As we age, or get injured, we have no way to grow new cartilage. Unlike humans and other mammals, the skeletons of sharks, skates, and rays are made entirely of cartilage and they continue to grow that cartilage throughout adulthood.

And new research published this week in eLife finds that adult skates go one step further than cartilage growth: They can also spontaneously repair injured cartilage. This is the first known example of adult cartilage repair in a research organism. The team also found that newly healed skate cartilage did not form scar tissue.

"Skates and humans use a lot of the same genes to make cartilage. Conceivably, if skates are able to make cartilage as adults, we should be able to also," says Andrew Gillis, senior author on the study and a Marine Biological Laboratory Whitman Center Scientist from the University of Cambridge, U.K.

The researchers carried out a series of experiments on little skates (Leucoraja erinacea) and found that adult skates have a specialized type of progenitor cell to create new cartilage. They were able to label these cells, trace their descendants, and show that they give rise to new cartilage in an adult skeleton.

Why is this important? There are few therapies for repairing cartilage in humans and those that exist have severe limitations. As humans develop, almost all of our cartilage eventually turns into bone. The stem cell therapies used in cartilage repair face the same issue--the cells often continue to differentiate until they become bone. They do not stop as cartilage. But in skates, the stem cells do not create cartilage as a steppingstone; it is the end result.

"We're looking at the genetics of how they make cartilage, not as an intermediate point on the way to bone, but as a final product," says Gillis.

The research is in its early stages, but Gillis and his team hope that by understanding what genes are active in adult skates during cartilage repair, they could better understand how to stop human stem-cell therapies from differentiating to bone.

Note: There is no scientific evidence that "shark cartilage tablets" currently marketed as supplements confer any health benefits, including relief of joint pain.

Reference:Marconi, A., Hancock-Ronemus, A., & Gillis, J. A. (2020). Adult chondrogenesis and spontaneous cartilage repair in the skate, Leucoraja erinacea. ELife, 9. doi:10.7554/elife.53414

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Strides in Medical Tourism Market Key Driver of Low-cost Patient Care in Globalized Healthcare Systems, Notes TMR – PR Newswire UK

ALBANY, New York, May 13, 2020 /PRNewswire/ -- The globalization of healthcare has been a key driver for consistently rising opportunities for all stakeholders in the global medical tourism market. Developing economies have been at the forefront of constantly expanding their clinical expertise and advanced technologies in medical services, notes Transparency Market Research. Their constant emphasis on offering patient care options that are comparable to those in developed nations is attracting revenues to the global medical tourism market.

The popularity of medical tourism is, to a large part, propelled by aggressive promotion and advertisement initiatives by healthcare institutions in medical tourism destinations.

Advances in National Health Care Systems of Developing Countries Play Crucial Role

Advances in protocols that expand the continuity of care for people who move outside their native countries have helped drive new technology developments in healthcare. The avenues have also emerged from people coming from less developed economies to a developing economy to access better health care. Clinicians, particularly doctors, from positive developments in national health care systems, imparting momentum to the expansion of the global medical tourism market.

The global medical tourism market stood at US$ 61.3 bn in 2018 and is projected to clock a CAGR of more than 10.5% from 2019 to 2027.

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Hospitals and specialty clinics have aimed at achieving compliance to global patient care standards, thus cementing the prospects in medical tourism. Healthcare institutions in recent years have been leaning to get certified by numerous non-profit organizations, such as Joint Commission International (JCI).

Countries with well-established infrastructures in North American and European countries, such as France, Italy and Germany, have been key contributors to the rapidly medical tourism in developing regions. Particularly the residents in the U.S. and the U.K. in recent years have been generating demand for healthcare services in emerging economies, thus propelling strides in medical tourism market. The trend has been observed due to several factors. One of the key factors is the high cost of patient care and more waiting times in developed countries of the world. The easing of regulations by governments in developing economies has facilitated their access to equally robust clinical expertise, albeit at much less cost.

On the other hand, Europe will also continue to contribute significant revenues, due to the presence of advanced medical treatments in the region.

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Constant upgrades in clinical expertise have enabled prominent markets to contribute substantial avenues in global medical tourism market. Post-procedure care and recuperation are also being constantly improved by deploying the state-of-the-art healthcare IT and patient-centered platforms in these markets.

Asia Pacific Key Regional Market; Presence of Healthcare Institutions Drive Demand

On the global front, Asia Pacific has emerged as the dominant market in 2019. It will gain more shares in relation to North America and Europe. Strides made in health care infrastructure of the region are helping the regional market gain shares. Further, the cost of surgery has come down substantially in the region. In Asia Pacific countries, the presence of doctors certified by regulatory agencies of the developed nations is increasing, thereby creating new demand in medical tourism market. The region has also benefitted from the rapidly growing array of studies in cancer patient care.

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On the other hand, the U.S., India, Israel, and Singapore have been hotbed of opportunities from the substantial demand for medical care for people suffering from cardiovascular disease (CVD). Rise in orthopedic surgeries in developing and developed regions from population residing in less developed countries will expand the horizon of opportunities in the medical tourism market.

Some of the well-entrenched players in the medical tourism market are Bahrain Specialist Hospital, Zulekha Healthcare Group, Hamad Medical Corporation, Dr. Soliman Fakeeh Hospital, Bumrungrad International Hospital, Apollo Hospitals Enterprise Limited, and Asklepios Kliniken GmbH.

The study presented here is based on a report by Transparency Market Research (TMR) titled "Medical Tourism Market (Medical Treatment - Cosmetology, Dentistry, Cardiology, Orthopedic surgery, Neurology, and Oncology) - Global Industry Analysis, Size, Share, Growth, Trends, and Forecast 2019 - 2027".

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The global medical tourism market is segmented based on:

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Covid-19 Detection Kits Market- The growth of the global covid-19 detection kits market relies on the responsiveness of countries to contain the spread of the coronavirus. The pandemic has wreaked havoc across the healthcare industry, and has led medical researchers to redirect all their might towards developing test kits and antidotes for coronavirus. The World Health Organization (WHO) declared the coronavirus as a global health emergency, following an outbreak of cases in several parts of the world. Currently, more than 180 countries have reported cases of coronavirus in individuals of all age groups.

Stem Cell Therapy Market -All stem cells are beneficial for medical research; however, each of the different kinds of stem cells has both limitations and promise. Embryonic stem cells that can be obtained from a very initial stage in human development have the prospect to develop all of the cell types in the human body. Adult stem cells are found in definite tissues in fully developed humans.

Platelet Rich Plasma and Stem Cell Alopecia Treatment Market- The global platelet rich plasma & stem cell alopecia treatment market is expected to reach a value of approximately US$ 450.5 Mn by the end of 2026, expanding at a high single digit CAGR during the forecast period. Factors such as increase in demand for accurate and prompt treatment of alopecia and advancements in platelet rich plasma and stem cell therapies that have revolutionized the diagnostic science are likely to boost the market.

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Strides in Medical Tourism Market Key Driver of Low-cost Patient Care in Globalized Healthcare Systems, Notes TMR - PR Newswire UK

Australia’s Mesoblast raises $90M to scale up stem cell therapy manufacturing to treat COVID-19 ARDS – BioWorld Online

PERTH, Australia Australian stem cell company Mesoblast Ltd. completed a capital raising of AU$138 million (US$90 million) to scale up manufacturing of its allogeneic cell therapy, remestemcel-L, to treat COVID-19 acute respiratory distress syndrome (ARDS).

The Melbourne-headquartered company is currently enrolling patients in a randomized placebo-controlled phase II/III trial in up to 300 patients across 30 sites in the U.S. The trial is evaluating whether remestemcel-L can reduce the high mortality in COVID-19 patients with moderate to severe ARDS.

Patients are being dosed, and were really pleased how fast enrollment is growing, Mesoblast CEO Silviu Itescu told BioWorld. Were right on target and hope to update the market soon.

The phase II/III trial was initiated after promising results were seen with remestemcel-L under an emergency compassionate-use protocol in COVID-19 ARDS at Mount Sinai Hospital in New York, where nine of 12 (75%) ventilator-dependent patients were able to come off ventilators within 10 days.

Under the compassionate-use protocol, patients in intensive care units received standard-of-care treatment. Once they were intubated on a ventilator, they were treated within 72 hours with two infusions of Mesoblasts remestemcel-L cells within five days.

Once youre ventilated when you have acute respiratory distress syndrome in the lungs, your likelihood of coming off a ventilator is 9%, and your survival is 12%, Itescu said.

Whats exciting is that our patients in the same epicenter of this disease with the same treatment everyone else is getting, suddenly 75% are coming off of ventilators within 10 days, and weve got 83% survival, Itescu said.

The compassionate-use treatment experience informed the design of the phase II/III trial, and the FDA approved the same protocol, but it is powered so that results will be self-evident, Itescu said.

The phase II/III trial will randomize up to 300 ventilator-dependent patients in intensive care units to either remestemcel-L or placebo on top of standard of care, in line with guidance provided by the FDA. The primary endpoint is all-cause mortality within 30 days of randomization, with the key secondary endpoint being the number of days alive and off mechanical support.

What people are dying of is acute respiratory distress syndrome, which is the bodys immune response to the virus in the lungs, and the immune system goes haywire, and in its battle with the virus it overreacts and causes severe damage to the lungs, he said.

Capital raise allows scale up for COVID-19 and influenza

The capital raise consisted of a placement of 43 million shares to existing and new institutional investors at a price of AU$3.20 per share, representing a 7% discount to the five-day volume-weighted average price (VWAP) at the close of trading May 8. The placement was conducted with Bell Potter Securities as lead manager and underwriter. Settlement is expected to occur on Friday, May 15.

Most of the funds raised will be used to scale up manufacturing of remestemcel-L for the treatment of critically ill patients suffering with diseases causing ARDS, including COVID-19 and influenza.

Were in the middle of a pandemic, and people are talking about opening up, and theyre talking about a potential second wave, Itescu said. Its too early to talk about projections, but we need to at least be in a position to make more product in an additional facility, so that requires technology transfer and certain process improvements.

Remestemcel-L is Mesoblasts lead product, and it is currently being studied in multiple indications so the move to ramp up manufacturing is a good strategic move regardless of COVID-19, he said.

There are at least 125,000 patients every year in the United States with influenza-related acute respiratory distress syndrome in intensive care units, and those patients have got about a 40% fatality rate. Up to about 60,000 patients die per year due to influenza ARDS, so even if COVID-19 magically disappears, which we could only hope, influenza is here to stay despite vaccines being available, the CEO said.

This product would work in the same way for influenza-related ARDS as it would for COVID-19-related ARDS, he said.

The ability to build out manufacturing capacity is part of an FDA requirement to be able to demonstrate it can make product for patients in the U.S.

The company already has a manufacturing facility in Singapore, and the additional site in the U.S. would give the company the ability to provide product globally.

Were putting our strategic plan into play. You need to have multiple geographies, especially in this kind of environment, Itescu said.

Without the cash, we wouldnt have been able to deliver on this, but we now can execute.

Mesoblast's allogeneic candidates are based on mesenchymal lineage cells collected from the bone marrow of healthy adult donors.

Remestemcel-L is currently being reviewed by the FDA for potential approval in the treatment of children with steroid-refractory acute graft-vs.-host disease (aGVHD). The company submitted the final module of a rolling BLA in January. The FDA has set a PDUFA date of Sept. 30 for the product branded as Ryoncil.

The clinical data submitted with the BLA showed a survival rate of 79% compared to an expected 30% survival rate in the pediatric phase III trial in aGVHD.

Remestemcel-L is also being developed for other rare diseases. Mesoblast is completing phase III trials in advanced heart failure and chronic low back pain.

Mesoblast shares (ASX:MSB) were down 1.45% on the news, trading at AU$3.39 per share by market close May 13. On Nasdaq (MESO), shares closed at $12.15.

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Australia's Mesoblast raises $90M to scale up stem cell therapy manufacturing to treat COVID-19 ARDS - BioWorld Online

CTX001 for Treatment of Sickle Cell Disease and Other Blood Disorders – Sickle Cell Anemia News

CTX001is an investigational therapy that Vertex Pharmaceuticals and CRISPR Therapeutics are developing to treat inherited disorders of hemoglobin such assickle cell diseaseandbeta-thalassemia.

Sickle cell disease is caused by a mutation in the HBB gene. This gene provides instructions to make the protein hemoglobin. Hemoglobin is a molecule inside red blood cells that is responsible for carrying oxygen. In sickle cell disease, the mutations result in missing or deficient hemoglobin.

CTX001 uses gene-editing technology to make a genetic change to increase the production of fetal hemoglobin in patients red blood cells. Fetal hemoglobin is a form of hemoglobin that exists naturally in newborn babies. The body later replaces it with the adult form of hemoglobin. However, sometimes fetal hemoglobin persists in adults, providing protection for people with sickle cell disease and beta-thalassemia.

For the treatment, researchers first collect a patients hematopoietic stem cells. These are cells from the bone marrow that give rise to all the red and white blood cells. They then genetically modify these cells in the laboratory so they are able to produce high levels of fetal hemoglobin. Finally, they reintroduce them into the patients body, where they will produce large amounts of red blood cells containing fetal hemoglobin.

Researchers presented the results of preclinical experiments with CTX001 at the American Society of Hematology (ASH) Annual Meeting in December 2017. CTX001 was able to efficiently edit the target gene in more than 90% of hematopoietic stem cells to achieve about 40% of fetal hemoglobin production. Investigators believe this is sufficient to improve a patients symptoms. Study results also showed that CTX001 affects only cells at the target site, thereby appearing to be a safe potential treatment.

These positive results prompted CRISPR topartner with Vertex to further develop CTX001. The goal is to market CTX001 as a gene-editing treatment for inherited hemoglobin disorders, including sickle cell disease and beta-thalassemia.

A Phase 1/2 clinical trial (NCT03745287) called CLIMB-SCD-121 was started in November 2018 to investigate the use of CTX001 in sickle cell disease. The open-label, multi-site, single-dose trial is recruiting 45 patients, ages 18 to 35, with severe sickle cell disease in the U.S., Canada, Belgium, Germany, and Italy. Researchers will give participants a single intravenous (into the bloodstream) infusion of CTX001. They will monitor the safety and effectiveness of the treatment for six months to two years.

Researchers reported preliminary results for the first patient in November 2019. Before treatment, the patient averaged seven vaso-occlusive crises (VOCs) a year. At four months after treatment, they were free of VOCs and had hemoglobin levels of 11.3 g/dL. The estimated completion date of the trial is May 2022.

The U.S. Food and Drug Administration (FDA) granted CTX001 fast track designationin January 2019. This designationallows for faster development and review of drugs that treat a serious medical issue and fill an unmet need.

In May 2020, the FDA also granted the therapy the designation of regenerative medicine advanced therapy (RMAT) for treating severe sickle cell disease and transfusion-dependent beta-thalassemia. The purpose of RMAT is to expedite the development and review of new therapies that treat serious or life-threatening medical conditions, or when they show significant clinical benefits over existing therapies.

Last updated: May 13, 2020

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Sickle Cell Disease News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.

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zge has a MSc. in Molecular Genetics from the University of Leicester and a PhD in Developmental Biology from Queen Mary University of London. She worked as a Post-doctoral Research Associate at the University of Leicester for six years in the field of Behavioural Neurology before moving into science communication. She worked as the Research Communication Officer at a London based charity for almost two years.

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Stem cells therapy A prospective treatment against coronavirus? – Daily Excelsior

Dr Shikha Sharma

Coronavirus disease (COVID-19) is an unforgettable word in 2020. World health organization has declared COVID-19 as pandemic and according to the Worldometer site, it has affected 212 countries and territories and has caused approximately 2.8 lakhs deaths so far. According to the various published scientific evidences COVID-19 is an infectious disease caused by new coronavirus that can lead to lung dysfunction. There are 7 coronaviruses that are known to cause disease in humans and among these 3 can cause the severe respiratory infection. These are severe acute respiratory syndrome coronavirus (SARS-CoV) identified in 2002 in China, Middle East respiratory syndrome coronavirus (MERS-CoV) identified in 2012 in Saudi Arabia and severe acute respiratory syndrome coronavirus2 (SARS-CoV2) commonly called COVID-19 identified in late 2019 in Wuhan, China. SARS-CoV, MERS-CoV and COVID-19 are closely related but COVID-19 spread more quickly than the other two. Over 8000 people from 29 different countries were affected with SARS-CoV epidemic during 2002-2004 while 40.78 lakhs people are affected with COVID-19 so far. In most cases, immune response (bodys defence system) triggered by the COVID-19 infection is sufficient to combat its pathogenesis leads to the recovery of patient. However, in some cases, COVID-19 infection causes highly inflammatory form of lung cells death and injury as the most dangerous phase of its pathogenesis which leads to the overproduction of inflammatory cytokines by bodys own immune cells creating cytokine storm that results in damage to the lung tissues causing pneumonia, acute respiratory distress syndrome (ARDS) and sepsis. In Pneumonia and ARDS air sac of lungs fill with fluid or pus. These complications lead to severe condition such as shortness of breath that require treatment with oxygen and ventilator. Therefore controlling inflammatory response is utmost important to prevent coronavirus lethality rate and for the longer life of a patient. Currently no specific treatment is available for COVID-19 infection but several vaccines, drugs and stem cells testing in various countries has generated hope to combat its pathogenesis. Recent breakthrough has demonstrated mesenchymal stem cells (MSCs) as cell medicine therapy to reduce COVID-19 infection.What are MSCsMSCs are multipotent adult stem cells that are capable of differentiating into various cell types such as fat cells, bone cells, liver cells, pancreatic cells, brain cells, heart cells and skin cells thus can participate in the repair and regeneration of various tissues and organs of the body. Inside the body, upon injury, MSCs migrate to the injured site and participate in the regeneration and repair of the organ either by differentiation or by paracrine secretion or both. In addition MSCs possess immunomodulatory and anti-inflammatory properties that contributes to its cell medicinal properties. MSCs can be isolated from various tissues such as bone marrow, peripheral blood, body fat, muscle, placenta, umbilical cord, umbilical cord blood, teeth and hair follicles and can be expanded ex vivo and used for transplantation for treating disease and disorders after genetic stability test.How MSCs reduce COVID-19pathogenesisAs reported by various research groups that upon intravenous injection or through mist inhalation the significant population of MSCs migrate to the lung and secrete various immunomodulatory and anti-inflammatory factors to cure lung dysfunction by normalizing immune response altered by COVID-19 and stimulate lung repair. Moreover MSCs are resistant to COVID-19 infection and can be used for autologous and allogenic transplantation.Clinical trial with MSCs for COVID-19There are several clinical trials registered with MSCs for the treatment of COVID-19 from various countries such as China, USA, UK, Germany, UAE, Jordan and Iran and some reports have been published. Approximately 100 patients have been treated with MSCs therapy from moderate to critical conditions within 10-15 days of transplantation. A first case treated with MSCs showed the recovery of 65 year old critical ill patient in Baoshan Peoples Hospital, Longling County, China. Initially the patient was treated with antiviral therapy and immunomodulator thymosin alpha1 but hasnt shown any recovery. Later after 10 days patient was diagnosed with severe pneumonia, acute respiratory distress syndrome, multiorgan injury, type2 diabetes, moderate anaemia, electrolyte disturbance, immunosuppression, acute gastrointestinal bleeding and other symptom was shifted to ICU and on ventilator. They showed that after three MSCs injections along with thymosin alpha1 lead to the recovery of patient from COVID-19 infection. FDA has approved 24 patient clinical trial in USA to test safety and efficacy of MSCs from umbilical cord to prevent COVID-19 infection. Recently, in USA three critically ill patients in ICU and on ventilator recovered from COVID-19 infection with MSCs treatment. An Israeli pharmaceutical company Pluristem therapeutics have tested MSCs therapy on 7 critically ill patient and found positive results. More recently, UAE also reported the treatment of 73 COVID-19 infected patients with stem cells. They have developed the technology to isolate the stem cells from patient blood, activate them and reintroduce them by mist inhalation. These reports are indicative that MSCs hold the potential to treat the COVID-19 infection by preventing bodys own defense system from overreacting and normalise its response to fight against COVID-19 infection. Many companies from different countries are seeking approval to begin clinical trial with stem cells against COVID-19 infection.Why are we lagging behind when we have stem cell companies/labs/facility in our country? We also produce GMP grade stem cells for transplantation. China tested the stem cell therapy on first patient when all other therapies failed and stem cells was one of option left to save the life of the patient. In India also so many deaths are happening due to COVID-19 we can also check if stem cells can reduce the mortality rate. Moreover as per some reports MSCs dont stay inside the body for more than 1-3 months and they eventually die and dont result in teratoma formation. Our government along with doctors and scientist can also formulate committee on stem cells and begin such initiative to test MSCs for the treatment of COVID-19 infection. Nevertheless, MSCs has joined the army along with the other possible interventions to prevent the COVID-19 illness.(The author is (PhD and Postdoc in Stem Cells)feedbackexcelsior@gmail.com

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Stem cells therapy A prospective treatment against coronavirus? - Daily Excelsior

Protocol Management, Off-the-Shelf Therapies Help Bring CAR T Into More Settings – Targeted Oncology

Carlos R. Bachier, MD

Chimeric antigen receptor (CAR) T-cell therapies quickly burst into the spotlight of hematology-oncology disease management because of their potential to illicit deep and durable responses from patients whose disease is relapsed or refractory to multiple previous lines of therapy. Relevant professional meetings and oncology publications exploded with research and news about CAR T cells, and this cellular therapy strategy is now being explored across hematologic and solid malignancies.

CAR T cells are a scientific revolution, Tania Jain, MBBS, assistant professor of oncology at Johns Hopkins University in Baltimore, Maryland, said in an interview with Targeted Therapies in Oncology (TTO). They have brought about a paradigm shift in terms of how were treating patients.

The 2 currently FDA-approved CAR T-cell therapies, axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah), are both indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma; additionally, tisagenlecleucel is approved for patients up to 25 years with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).1-3 With a second wave of approvals likely on the horizon for therapies such as lisocabtagene maraleucel (liso-cel) and idecabtagene vicleucel (bb2121), CAR T is gaining traction and will likely play an increasingly prominent role in the future treatment paradigm in oncology.

CAR T-cell therapy administration is largely limited to the inpatient setting at both academic institutions and large accredited cancer centers, making such treatments unavailable to most patients. Other challenges with this type of therapy include its potential to cause serious toxicities resulting in organ damage and death.4

David G. Maloney, MD, PhD

Due to the promising efficacy of these agents, investigators have been working toward viable solutions to bring CAR T-cell therapies to more patients by alleviating difficulties associated with therapy delivery and patient care.

CAR T-cell therapies, both those currently approved and the many being explored in late-phase clinical trials, are produced from autologous T cells obtained from the patient receiving therapy. This personalization has led to tremendous success, yet it is a large part of why CAR T-cell therapy use remains limited to a select group of patients.

Time is an important consideration for patients who have experienced multiple relapses and may be too weakened by numerous lines of prior therapy to wait several weeks for the CAR T-cell manufacturing process. The effects of previous treatments or the disease itself can also present challenges, as manypatients are rendered lymphopenic and may be unable to produce enough T cells for harvesting. Roadblocks may remain for patients who are not limited by these factors; manufacturing success and effectiveness of the CAR T-cell product can be negatively influenced by disease-related dysfunctions of patients T cells.4

A new option, off-the-shelf CAR T-cell products, may help solve these problems. These premade products are manufactured using allogeneic donor cells (instead of autologous cells from the patient), and they present immediate advantages to clinicians, such as immediate availability, opportunity for product standardization, and decreased cost.5

The advantages [include] being able to access the cellular therapy in real time, as opposed to autologous products that havetobe manufactured,Craig S. Sauter, MD, clinical director of the Adult Bone Marrow Transplant Service at Memorial Sloan Kettering Cancer Center in New York, New York, explained in an interview withTTO. This is particularly important for patients who are not responding to therapy, which is a current requirement for treatment with CAR T cells, he added.

Findings from a phase I trial (NCT01430390) in patients with relapsed or refractory B-cell malignancies showed that patients with non-Hodgkin lymphoma (NHL) experienced durable responses with an Epstein-Barr virusspecific cytotoxic lymphocyte CAR product derived from cells harvested from third-party donors (rather than from their more precisely matched stem cell donors). All 4 patients with NHL and a single patient with chronic lymphocytic leukemia, who were treated with third-party cells, remained disease free and alive at the time of analysis, with a median follow-up of over 2 years.6

The advantages [of this type of therapy are] that it eliminates the need for apheresis [and] shipping cellular products back and forth. [Instead, clinicians] have a pharmaceutical product on the shelf for access, Sauter, who was an author on the trial, said. Another notable product being investigated in clinical trials is UCART19, an allogeneic engineered anti CD19CAR T-cell product, which is being evaluated in the phase I CALM trial in adult patients with relapsed or refractory B-cell ALL (NCT02746952) and in the phase I PALL trial of pediatric patients with relapsed or refractory CD19-positive B-cell ALL (NCT02808442). Other off-the-shelf agents are described in theTABLE.5

Issues with inpatient CAR T-cell therapy administrationinclude high demands on health care resources and strain on patients and their families. Moving treatment to the outpatient setting has the potential to reduce this strain; however,clinicians taking over care of patients receiving CAR T-cell therapy must be prepared with the proper resources to identify and manage adverse events associated with therapy.

One of the most notable risks to patients receiving CAR T-cell therapy is cytokine release syndrome (CRS), a systemic inflammatory response that is characterized by increased serum levels of inflammatory cytokines, fever, hypotension, hypoxia, and organ dysfunction.4 [CAR T] can also lead to neurological events and can cause confusion and, in some patients, seizures,Carlos R. Bachier, MD, Director of Cellular Research at Sarah Cannon Cancer Center in Nashville, Tennessee, explained in an interview with TTO.

Regardless of the infusion setting, patients require close monitoring in the hours and days following therapy administration. A review byLucrecia Yez, PhD, MS, and colleagues stated that key criteria for treating patients in the outpatient setting include an educated caregiver and necessary infrastructure allowing for outpatient visits plus adequate emergency and intensive care unit (ICU) access. Patients followed as outpatients must be given twice-daily temperature checks for a minimum of 14 days following treatment and preferably extending up to 3 to 4 weeks following infusion. Anysigns of back pain, skin rash, dizziness, chills, shortness of breath, chest pain, tachycardia, or neurological events that may indicate neurotoxicity or signs of CRS must be reported immediately so treatment can begin as quickly as possible.7

Because of the risk of CRS and neurotoxicity, both FDA-approved agents are restricted under the Risk Evaluation and Mitigation Strategy, an FDA-mandated program that builds in caution for use of agents with serious safety concerns.8,9 Therefore, 2 doses of tocilizumab (Actemra), an interleukin (IL)-6 receptor antagonistthat was approved in 2017 for management of CRS associated with CAR T-cell therapy,1,4 should be on hand for each patient before the infusion of CAR T cells. Steroids have also demonstrated efficacy against CRS, but concernssurrounding CAR T-cell suppression with these agents have established them as a second-line choice after tociluzumab.9

Immune effector cellassociated neurotoxicity syndrome (ICANS) is a group of neurologic symptoms associated with treatments such as CAR T-cell therapy. Predisposing factors include younger age, higher tumor burden, high levels of pretreatment inflammation, and history of early or high-grade CRS. Treatments for complications of ICANS vary. Some centers may prescribe prophylactic antiepileptic medications, such as levetiracetam, to prevent seizures in patients with grade 2 or higher neurologic events. AntiIL-6 therapy can be considered in patients with concurrent CRS, but corticosteroids are the preferred regimen in those with neurotoxicity alone.9

In February of this year, the investigational CAR T-cell product liso-cel was granted priority review by the FDA for the treatment of adult patients with relapsed or refractory large B-cell lymphoma who had undergone at least 2 prior therapies.10 Investigators believe that liso-cel therapy may have a place in a broad range of patients and in the outpatient setting.11

It turns out liso-cel has a low incidence of [CRS and ICANS], and they occurred relatively late compared with other products, said Bachier. Because of this low incidence, the strategy was to deliver liso-cel in an outpatient setting.

The feasibility of liso-cel administration on an outpatient basiswas evaluatedby Bachier and colleagues, and the results were presented at the 2020 Transplantation & Cellular Therapy Meetings of the American Society for Transplantation and Cellular Therapy and the Center for International Blood & Marrow Transplant Research, held February 19 to 23, 2020, in Orlando, Florida.12

The authors analyzed data from 3 clinical trials of liso-cel, with a focus on the subset of participants who were treated as outpatients. The included trials were the phase I TRANSCEND-NHL-001 (NCT02631044) and phase II OUTREACH (NCT03744676) trials in patientswhohadundergone at least 2 lines of prior treatment, as well as the PILOT study (NCT03483103), which examined liso-cel as second-line therapy in patients who were ineligible for autologous hematopoietic stem cell transplant because of age, organ function, or ECOG performance score. All 3 studies allowed outpatienttreatment, with some patients receiving their therapy in the nonuniversity setting.

This clinical trial included sites that were not a part of a university but had experience treating patients for stem cell transplant, Bachier said. Some of these sites that participated were notyour traditional university centers that had traditionally been involved in the development of these therapies.

Much caution was required in order to maximize patient safety and treatment efficacy. The approach of doing CAR T-cell therapy, in general, in the outpatient setting requires a robust clinical ability of the centers, said coauthor David G. Maloney, MD, PhD, medical director of Cellular Immunotherapy at the Immunotherapy Integrated Research Center of Fred Hutchinson Cancer Research Center in Seattle, Washington, in an interview. We were able to get people safely to the hospital, and it was rare that you would have to do escalation of care when people were admitted. Most of the time, patients could bemanagedand wereout of the ICU, withrare exceptions. But again, you still have to have the wherewithal to get patients to the ICU pot entially for aggressive care if needed.

Results of the analysis of outpatient data from the 3 trials showed that rates of toxicity and response were similar to those previously reported for the entire patient cohort (both inpatients and outpatients) of the TRANSCEND-NHL-001 trial.

Based on these results, the indication is that you can deliver [liso-cel] in the outpatient setting and the outcomes are good compared with those treated in the inpatient setting, said Bachier. Aside from that, it also showed that liso-cel could be safely administered outside of university programs and in more community-based programs, most of them being aligned [with] or part of stem cell and bone marrow transplant programs.

When planning or setting up a CAR T-cell therapy outpatient program, investigators anticipate possible barriers to successfultreatment. The greatest barrier, according to Bachier, is access to physicians and staff who are knowledgeable and trained to manage toxicities related to CART-cell therapy. These therapies still should not, in my opinion, be delivered [by clinicians in] community centers that do not have the expertise to deliver the therapies safely, he said.

Maloney added that centers should be required to have the ability to triage patients 24/7 and allow for patients to be directly admitted to the hospital if needed. In the case of the analysis of outpatient data from the 3 liso-cel trials however, he said, We found that around 30% to 40% of patients did not actually ever require hospitalization, whichis quite interesting. Most of the 60% to 70% of patients who were hospitalized were admitted for fever, he added.

In addition, sites must gain accreditation and approval, Jain pointed out.

Every center that intends to do CAR T-cell therapy is first approved by each of the companies [that manufacturethese agents], Jain said. The centers also have to be approved by FACT [Foundation for the Accreditation of Cellular Therapy], which is the same organization that approves centers for allogeneic stem cell transplant. These are some of the largest things that a center needs to go through, which takes care of things like developing standard practices and other guidelines to make sure that these [therapies] are used safely and appropriately.

As investigators and oncologists explore the feasibility of moving CAR T-cell therapy into more settings, 2 questions arise: What settings have on this therapy?

What type of training and skills do clinicians need? Like other clinicians, Sauter has concerns about new allogeneic cellular therapies,andhe hopes future research will focus on mitigating these challenges. The concern would be that these are not autologous products and there is the risk of rejection from the host immune system, he said. Strategies to circumnavigate that risk are at the forefront of investigationin off-the-shelf CAR T cells.

The research is not stopping with CAR T-cell therapy,though. Were seeing a lot of new molecules coming in that will be challenging the roles of CAR T cells, [such as] specific antibodies, which may even work in cases of CAR T-cell failure, Maloney said. We are still learning how to make those more effective and safer.

References:

1. FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine releasesyndrome.FDAwebsite.PublishedAugust30,2017.AccessedApril14, 2020. bit.ly/2RC4eQ8

2. FDA approves axicabtagene ciloleucel for large B-cell lymphoma. FDA website. Published October 18, 2017. Accessed April 14, 2020. bit.ly/2yYIQOp

3. FDA approves tisagenlecleucel for adults with relapsed or refractory large B-cell lymphoma. FDA website. Published May 1, 2018. Accessed April 14, 2020. bit.ly/34zPoi8

4. Rafiq S, Hackett CS, Brentjens RJ. Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nat Rev Clin Oncol. 2020;17(3):147167. doi: 10.1038/s41571-019-0297-y

5. DepilS,DuchateauP,GruppSA,MuftiG,PoirotL.Off-the-shelfallogeneic CAR T cells: development and challenges. Nat Rev Drug Discov. 2020;19(3):185199. doi: 10.1038/s41573-019-0051-2

6. Curran KJ, Sauter CS, Kernan CS, et al. Durable remission following off-theshelf chimeric antigen receptor (CAR) T-cells in patients with relapse/refractory (R/R) B-cell malignancies. Presented at: 2020 Transplantation & Cellular Therapy Meetings; February 19-23, 2020; Orlando, FL. Abstract 120. bit.ly/2ufDYCu

7. Yez L, Snchez-Escamilla M, Perales MA. CAR T cell toxicity: current managementandfuturedirections. Hemasphere.2019;3(2):e186.doi:10.1097/ HS9.0000000000000186

8. Risk evaluation and mitigation strategies | REMS. FDA website. Updated August 8, 2019. Accessed April 14, 2020. bit.ly/2ykhLVt

9. JainT,BarM,KansagraAJ,etal.UseofchimericantigenreceptorTcell therapy in clinical practice for relapsed/refractory aggressive B cell non-Hodgkin lymphoma: an expert panel opinion from the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant. 2019;25(12):2305-2321. doi: 10.1016/j.bbmt.2019.08.015

10. U.S. Food and Drug Administration (FDA) accepts for Priority Review Bristol-Myers Squibbs Biologics License Application (BLA) for lisocabtagene maraleucel (liso-cel) for adult patients with relapsed or refractory large B-cell lymphoma. News release. Bristol-Myers Squibb; February 12, 2020. Accessed April 15, 2020. bit.ly/37ruQbs

11. Helwick C. Strong activity shown for lisocabtagene maraleucel CAR T-cell therapy in aggressive large B-cell lymphoma. ASCO Post website. Published February 25, 2020. Accessed April 15, 2020. bit.ly/3eoD0pT

12. Bachier CR, Palomba ML, Abramson JA, et al. Outpatient treatment with lisocabtagene maraleucel (liso-cel) in 3 ongoing clinical studies in relapsed/refractory (R/R) large B cell non-Hodgkin lymphoma (NHL), including second-line transplant noneligible (TNE) patients: TRANSCEND NHL 001, OUTREACH, and PILOT. Presented at: 2020 Transplantation & Cellular Therapy Meetings; February 19-23, Orlando, FL. Abstract 29. bit.ly/37I7DC9

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Protocol Management, Off-the-Shelf Therapies Help Bring CAR T Into More Settings - Targeted Oncology

BrainStorm Leases a New Cleanroom Facility at The Tel Aviv Sourasky Medical Center to Manufacture NurOwn for The European Union – Yahoo Finance

NEW YORK, N.Y., and TEL AVIV, Israel, May 07, 2020 (GLOBE NEWSWIRE) -- BrainStorm Cell Therapeutics Inc. (NASDAQ: BCLI), a leading developer of adult stem cell therapies for neurodegenerative diseases, announced today a lease agreement with the Tel Aviv Sourasky Medical Center (Sourasky)in Tel Aviv, Israel, to produce NurOwn in three state-of-the-art cleanrooms. The new facility will significantly increase the Companys capacity to manufacture and ship its product into the European Union and the local Israeli market. The cleanroom facility is part of Souraskys Institute for Advanced Cellular Therapies.

"Sourasky Hospital is a leader in the advancement and manufacturing of cell and gene therapy products and is well-equipped to rapidly scale up and produce NurOwn," stated Prof. Ronni Gamzu, CEO of Tel Aviv Sourasky Medical Center. "We look forward to continuing our work with BrainStorm to bring NurOwn to ALS patients and help fulfill the clinical therapy demands for the Companys pipeline programs.

"Sourasky Hospital, known for introducing pioneering solutions into clinical practice and advancing patient care, has a first rate team with the proven experience to produce regenerative products in accordance to the highest standard of cGMP manufacturing," said Chaim Lebovits, CEO of BrainStorm. "This agreement will ensure that we can provide NurOwn to patients after regulatory approval, not only in Israel but we have secured capacity to rapidly scale up production as we advance our investigational treatment across the European Union. We are very pleased to be able to expand our ongoing collaboration with Sourasky Hospital, one of the worlds most innovative and respected medical centers."

About NurOwn NurOwn (autologous MSC-NTF) cells represent a promising investigational therapeutic approach to targeting disease pathways important in neurodegenerative disorders. MSC-NTF cells are produced from autologous, bone marrow-derived mesenchymal stem cells (MSCs) that have been expanded and differentiated ex vivo. MSCs are converted into MSC-NTF cells by growing them under patented conditions that induce the cells to secrete high levels of neurotrophic factors. Autologous MSC-NTF cells can effectively deliver multiple NTFs and immunomodulatory cytokines directly to the site of damage to elicit a desired biological effect and ultimately slow or stabilize disease progression. BrainStorm has fully enrolled a Phase 3 pivotal trial of autologous MSC-NTF cells for the treatment of amyotrophic lateral sclerosis (ALS). BrainStorm also recently received U.S. FDA acceptance to initiate a Phase 2 open-label multicenter trial in progressive MS and enrollment began in March 2019.

About BrainStorm Cell Therapeutics Inc. BrainStorm Cell Therapeutics Inc. is a leading developer of innovative autologous adult stem cell therapeutics for debilitating neurodegenerative diseases. The Company holds the rights to clinical development and commercialization of the NurOwn technology platform used to produce autologous MSC-NTF cells through an exclusive, worldwide licensing agreement. Autologous MSC-NTF cells have received Orphan Drug status designation from the U.S. Food and Drug Administration (U.S. FDA) and the European Medicines Agency (EMA) in ALS. BrainStorm has fully enrolled a Phase 3 pivotal trial in ALS (NCT03280056), investigating repeat-administration of autologous MSC-NTF cells at six U.S. sites supported by a grant from the California Institute for Regenerative Medicine (CIRM CLIN2-0989). The pivotal study is intended to support a filing for U.S. FDA approval of autologous MSC-NTF cells in ALS. BrainStorm also recently received U.S. FDA clearance to initiate a Phase 2 open-label multicenter trial in progressive Multiple Sclerosis. The Phase 2 study of autologous MSC-NTF cells in patients with progressive MS (NCT03799718) started enrollment in March 2019. For more information, visit the company's website at http://www.brainstorm-cell.com

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

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CONTACTS

Investor Relations:Preetam Shah, MBA, PhDChief Financial OfficerBrainStorm Cell Therapeutics Inc.Phone: + 1.862.397.1860pshah@brainstorm-cell.com

Media:Sean LeousWestwicke/ICR PRPhone: +1.646.677.1839sean.leous@icrinc.com

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BrainStorm Leases a New Cleanroom Facility at The Tel Aviv Sourasky Medical Center to Manufacture NurOwn for The European Union - Yahoo Finance

CRISPR Therapeutics and Vertex Pharmaceuticals Announce FDA Regenerative Medicine Advanced Therapy (RMAT) Designation Granted to CTX001 for the…

ZUG, Switzerland and CAMBRIDGE, Mass. and BOSTON, May 11, 2020 (GLOBE NEWSWIRE) -- CRISPR Therapeutics (Nasdaq: CRSP) and Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced that the U.S. Food and Drug Administration (FDA) granted Regenerative Medicine Advanced Therapy (RMAT) designation to CTX001, an investigational, autologous, gene-edited hematopoietic stem cell therapy, for the treatment of severe sickle cell disease (SCD) and transfusion-dependent beta thalassemia (TDT).

RMAT designation is another important regulatory milestone for CTX001 and underscores the transformative potential of a CRISPR-based therapy for patients with severe hemoglobinopathies, said Samarth Kulkarni, Ph.D., Chief Executive Officer of CRISPR Therapeutics. We expect to share additional clinical data on CTX001 in medical and scientific forums this year as we continue to work closely with global regulatory agencies to expedite the clinical development of CTX001.

The first clinical data announced for CTX001 late last year represented a key advancement in our efforts to bring CRISPR-based therapies to people with beta thalassemia and sickle cell disease and demonstrate the curative potential of this therapy, said Bastiano Sanna, Ph.D., Executive Vice President and Chief of Cell and Genetic Therapies at Vertex. We are encouraged by these recent regulatory designations from the FDA and EMA, which speak to the potential impact this therapy could have for patients.

Established under the 21st Century Cures Act, RMAT designation is a dedicated program designed to expedite the drug development and review processes for promising pipeline products, including genetic therapies. A regenerative medicine therapy is eligible for RMAT designation if it is intended to treat, modify, reverse or cure a serious or life-threatening disease or condition, and preliminary clinical evidence indicates that the drug or therapy has the potential to address unmet medical needs for such disease or condition. Similar to Breakthrough Therapy designation, RMAT designation provides the benefits of intensive FDA guidance on efficient drug development, including the ability for early interactions with FDA to discuss surrogate or intermediate endpoints, potential ways to support accelerated approval and satisfy post-approval requirements, potential priority review of the biologics license application (BLA) and other opportunities to expedite development and review.

In addition to RMAT designation, CTX001 has received Orphan Drug Designation from the U.S. FDA for TDT and from the European Commission for TDT and SCD. CTX001 also has Fast Track Designation from the U.S. FDA for both TDT and SCD.

About CTX001CTX001 is an investigational ex vivo CRISPR gene-edited therapy that is being evaluated for patients suffering from TDT or severe SCD in which a patients hematopoietic stem cells are engineered to produce high levels of fetal hemoglobin (HbF; hemoglobin F) in red blood cells. HbF is a form of the oxygen-carrying hemoglobin that is naturally present at birth and is then replaced by the adult form of hemoglobin. The elevation of HbF by CTX001 has the potential to alleviate transfusion requirements for TDT patients and painful and debilitating sickle crises for SCD patients. CTX001 is the most advanced gene-editing approach in development for beta thalassemia and SCD.

CTX001 is being developed under a co-development and co-commercialization agreement between CRISPR Therapeutics and Vertex.

About the CRISPR-Vertex CollaborationCRISPR Therapeutics and Vertex entered into a strategic research collaboration in 2015 focused on the use of CRISPR/Cas9 to discover and develop potential new treatments aimed at the underlying genetic causes of human disease. CTX001 represents the first treatment to emerge from the joint research program. CRISPR Therapeutics and Vertex will jointly develop and commercialize CTX001 and equally share all research and development costs and profits worldwide.

About CRISPR TherapeuticsCRISPR Therapeutics is a leading gene editing company focused on developing transformative gene-based medicines for serious diseases using its proprietary CRISPR/Cas9 platform. CRISPR/Cas9 is a revolutionary gene editing technology that allows for precise, directed changes to genomic DNA. CRISPR Therapeutics has established a portfolio of therapeutic programs across a broad range of disease areas including hemoglobinopathies, oncology, regenerative medicine and rare diseases. To accelerate and expand its efforts, CRISPR Therapeutics has established strategic partnerships with leading companies including Bayer, Vertex Pharmaceuticals and ViaCyte, Inc. CRISPR Therapeutics AG is headquartered in Zug, Switzerland, with its wholly-owned U.S. subsidiary, CRISPR Therapeutics, Inc., and R&D operations based in Cambridge, Massachusetts, and business offices in San Francisco, California and London, United Kingdom. For more information, please visit http://www.crisprtx.com.

CRISPR Forward-Looking StatementThis press release may contain a number of forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including statements regarding CRISPR Therapeutics expectations about any or all of the following: (i) the status of clinical trials (including, without limitation, the expected timing of data releases) and discussions with regulatory authorities related to product candidates under development by CRISPR Therapeutics and its collaborators, including expectations regarding the benefits of RMAT designation; (ii) the expected benefits of CRISPR Therapeutics collaborations; and (iii) the therapeutic value, development, and commercial potential of CRISPR/Cas9 gene editing technologies and therapies. Without limiting the foregoing, the words believes, anticipates, plans, expects and similar expressions are intended to identify forward-looking statements. You are cautioned that forward-looking statements are inherently uncertain. Although CRISPR Therapeutics believes that such statements are based on reasonable assumptions within the bounds of its knowledge of its business and operations, forward-looking statements are neither promises nor guarantees and they are necessarily subject to a high degree of uncertainty and risk. Actual performance and results may differ materially from those projected or suggested in the forward-looking statements due to various risks and uncertainties. These risks and uncertainties include, among others: the potential impacts due to the coronavirus pandemic, such as the timing and progress of clinical trials; the potential for initial and preliminary data from any clinical trial and initial data from a limited number of patients (as is the case with CTX001 at this time) not to be indicative of final trial results; the potential that CTX001 clinical trial results may not be favorable; that future competitive or other market factors may adversely affect the commercial potential for CTX001; uncertainties regarding the intellectual property protection for CRISPR Therapeutics technology and intellectual property belonging to third parties, and the outcome of proceedings (such as an interference, an opposition or a similar proceeding) involving all or any portion of such intellectual property; and those risks and uncertainties described under the heading "Risk Factors" in CRISPR Therapeutics most recent annual report on Form 10-K, and in any other subsequent filings made by CRISPR Therapeutics with the U.S. Securities and Exchange Commission, which are available on the SEC's website at http://www.sec.gov. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date they are made. CRISPR Therapeutics disclaims any obligation or undertaking to update or revise any forward-looking statements contained in this press release, other than to the extent required by law.

About VertexVertex is a global biotechnology company that invests in scientific innovation to create transformative medicines for people with serious diseases. The company has multiple approved medicines that treat the underlying cause of cystic fibrosis (CF) a rare, life-threatening genetic disease and has several ongoing clinical and research programs in CF. Beyond CF, Vertex has a robust pipeline of investigational small molecule medicines in other serious diseases where it has deep insight into causal human biology, including pain, alpha-1 antitrypsin deficiency and APOL1-mediated kidney diseases. In addition, Vertex has a rapidly expanding pipeline of genetic and cell therapies for diseases such as sickle cell disease, beta thalassemia, Duchenne muscular dystrophy and type 1 diabetes mellitus.

Founded in 1989 in Cambridge, Mass., Vertex's global headquarters is now located in Boston's Innovation District and its international headquarters is in London, UK. Additionally, the company has research and development sites and commercial offices in North America, Europe, Australia and Latin America. Vertex is consistently recognized as one of the industry's top places to work, including 10 consecutive years on Science magazine's Top Employers list and top five on the 2019 Best Employers for Diversity list by Forbes. For company updates and to learn more about Vertex's history of innovation, visit http://www.vrtx.com or follow us on Facebook, Twitter, LinkedIn, YouTube and Instagram.

Vertex Special Note Regarding Forward-Looking StatementsThis press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including, without limitation, the information provided regarding the status of, and expectations with respect to, the CTX001 clinical development program and related global regulatory approvals, and expectations regarding the RMAT designation. While Vertex believes the forward-looking statements contained in this press release are accurate, these forward-looking statements represent the company's beliefs only as of the date of this press release and there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that the development of CTX001 may not proceed or support registration due to safety, efficacy or other reasons, and other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through the company's website at http://www.vrtx.com. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

(VRTX-GEN)

CRISPR Therapeutics Investor Contact:Susan Kim, +1 617-307-7503susan.kim@crisprtx.com

CRISPR Therapeutics Media Contact:Rachel EidesWCG on behalf of CRISPR+1 617-337-4167 reides@wcgworld.com

Vertex Pharmaceuticals IncorporatedInvestors:Michael Partridge, +1 617-341-6108orZach Barber, +1 617-341-6470orBrenda Eustace, +1 617-341-6187

Media:mediainfo@vrtx.com orU.S.: +1 617-341-6992orHeather Nichols: +1 617-961-0534orInternational: +44 20 3204 5275

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CRISPR Therapeutics and Vertex Pharmaceuticals Announce FDA Regenerative Medicine Advanced Therapy (RMAT) Designation Granted to CTX001 for the...

Study: Want to lose weight? Get rid of that pesky nose – The Big Smoke Australia

An American study has discovered the link between a sense of smell and the rolls under ones chin. In fact, the better it smells, the fewer calories we burn.

We all have that friend, that one friend who tells you about how just the smell of food makes them put on weight, before they dig into their kale packed quinoa super salad. Much as it may hurt you to strain a disingenuous laugh at your fitness-savvy friend, there may actually be some truth to their done to death office room joking.

Researchers at the University of California Berkeley have found that obese mice who have lost their sense of smell do in fact lose weight.

Surely thats because without their ability to sniff out their delicious fatty food which one can only assume is some kind of deep-fried cheese, and not the local RatDonalds, or similar rodent-based fast-food chain bulkier mice lose any desire to eat their problems away, right?

Interestingly enough, thats not exactly right.

These nostril-y lacking mice ate just as much fatty food as their normally smelling peers, yet only the mice that retained their sense of smell gained any weight. Whats more, mice that were given a boosted sense of smell perhaps the most useless superpower one could ever hope for grew even fatter on the same high-fat diet than ordinarily nosed mice.

This suggests that the odour of our food has great importance in how our bodies deal with calories. If you were to lose your ability to smell your food, much like our rodent friends above, your body may burn it, rather than store it.

The results of this study show a key connection between the olfactory (or smell) system and regions of the brain that regulates metabolism, particularly the hypothalamus.

It should be noted, however, that the neural circuits involved are still unknown.

Cline Riera, a former UC Berkeley postdoctoral fellow now at Los Angeles Cedars-Sinai Medical Centre, described the study as one of the first that demonstrates how we can actually alter how the brain perceives energy balance, and how the brain regulates energy balance, by manipulating olfactory inputs our noses.

Indeed, humans who lose their sense of smell because of age, injury or diseases such as Parkinsons often become anorexic, but until this point, the cause has been unclear. This is because loss of pleasure in eating also leads to depression, which in itself can cause a loss of appetite.

This study, published in this weeks Cell Metabolism journal, indicates the loss of smell itself plays a role, and suggests possible interventions for both those who have lost their sense of smell as well as those having trouble losing weight.Sensory systems play a role in metabolism, explains senior author Andrew Dillin, the Thomas and Stacey Siebel Distinguished Chair in Stem Cell Research, professor of molecular and cell biology and Howard Hughes Medical Institute Investigator.

Weight gain isnt purely a measure of the calories taken in; its also related to how those calories are perceived.

If we can validate this in humans, perhaps we can actually make a drug that doesnt interfere with smell but still blocks that metabolic circuitry. That would be amazing.

Riera notes that mice, like humans, are more sensitive to smells when they are hungry than after they have eaten, and that as a result, it is possible that the lack of smell tricks the body into thinking it has already eaten. While we search for food, our bodies store calories in case it is unsuccessful. Once food has been successfully found, however, our bodies feel free to burn those calories away.

In order to avoid condemning their furry friends to a scent free life, researchers made use of gene therapy to destroy olfactory neutrons in the mices noses, while sparing their stem cells.

This meant the mice would only lose their sense of smell for about three weeks, before the olfactory neutrons regret. The mice turned their beige fat cells the subcutaneous fat storage cells that accumulate around our thighs and midriffs into brown fat cells, which burn fatty acids to produce heat.

In fact, some turned almost all of their beige fat into brown fat, making them as lean as any of your workplace gym junkies.

White fat cells the storage cells that cluster around our internal organs and are associated with poor health outcomes also shrank in size.

The formerly chunky mice, which had also developed glucose intolerance a condition that leads to diabetes also regained normal glucose tolerance, in addition to their weight loss.

Its not all good news, though. The loss in smell was accompanied by a large increase in levels of the hormone noradrenaline: a stress response tied to the sympathetic nervous system.

In humans, this sustained hormone rise could lead to a heart attack.

As Dillin notes, though eliminating smell in humans wanting to lose weight would be a drastic step to take, it could be a viable alternative for morbidly obese people contemplating stomach stapling or bariatric surgery, even in spite of the increase noradrenaline line.

For that small group of people, you could wipe out their smell for maybe six months and then let the olfactory neutrons grow back, after theyve got their metabolic program reworked.

Dillon and Riera developed two different techniques in blocking the sense of smell in adult mice one involving genetically engineering mice to express a diphtheria receptor in their olfactory neutrons, which reach from the noses odour receptors to the olfactory centre in the brain.

When diphtheria toxin was sprayed into their nose, the neurons died, rendering the mouse smell-free until their stem cells regenerated them.

In method two, they engineered a benign virus to carry the receptor into olfactory cells only via inhalation. Once inhaled, the diphtheria toxin would again take down their sense of smells for around three weeks.Regardless of how the mouse lost their sense of smell, they ate the same amount of high-fat food as their scent appreciative cousins.

However, while the smell-deficient mice gained at most 10 per cent more weight going from 25-30 grams to 33 grams the stock standard mice gained about 100 per cent of their normal weight, climbing up to 60 grams and giving up any hope of a summer beach bod.

The smell-free mice retained a normal insulin sensitivity and response to glucose both of which are disrupted in metabolic disorders like obesity.

Better still, mice that were already chunky lost weight after their smell was knocked out, slimming down to the size of normal mice while still eating their high-fat diet. Only fat weight was lost, with no impact on muscle, organ or bone mass.

The UC Berkeley researchers then teamed up with colleagues in Germany who had developed a super smelling strain of mice, complete with more acute olfactory nerves, where they made the discovery of their increase in weight gain.

People with eating disorders sometimes have a hard time controlling how much food they are eating and they have a lot of cravings, explained Riera.

We think olfactory neurons are very important for controlling pleasure of food, and if we have a way to modulate this pathway, we might be able to block cravings in these people and help them with managing their food intake.

Of course, before you go rushing to your shed in hopes of removing your bothersome nose, it should be noted that research is still ongoing, and that mice are, believe it or not, not identical to your average human being.

Still, if all it takes to meet your shredding goals is a few weeks without your overrated sense of smell, it might be time to cancel that gym membership.

Again.

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Study: Want to lose weight? Get rid of that pesky nose - The Big Smoke Australia

Region 3: Immune and Cellular Tx, Part II – MedPage Today

Fill out your #OncMadness 2020 bracket here. And learn more.

CAR-T in Hematologic Cancers

Targeting cancer via immunomodulation has been the holy grail of oncology. Over the last few years, the hottest topic in hematology has been chimeric antigen receptor (CAR) T-cell therapy, or CAR-T.

To discuss the development of CAR T-cell therapy, one must look back at the fascinating history of Carl June, MD. In the 1980s, when so many Americans were partying like it was 1999, June began his journey to become an oncologist. Researchers had learned that in patients with an identical twin, leukemia could be cured via high-dose chemotherapy followed by a bone marrow transplant. But most patients didn't have a twin, so hematologists had to identify a best match. Given their different immune systems, patients began experiencing graft-versus-host disease.

June began working on a way to achieve the same benefits of a transplant, without the transplant. His approach, using patients' own immune systems, took much teamwork and about 30 years to develop.

To hear June share his memories is fascinating. Given that he was in the Navy, he learned about radiation-induced bone marrow failure from victims of Chernobyl. The Navy wanted to learn how to replenish immune systems post-radiation exposure, so he set about doing this.

As geopolitical pressures changed and the likelihood of nuclear war decreased, June and his team shifted their focus to rebuilding T-cell populations in patients with HIV and AIDS. They harvested T cells from patients, amplified them, and infused them back into patients. He recalls being shocked that it worked!

In 1999, June joined the faculty of the University of Pennsylvania and resumed studying leukemia, now applying his work in HIV to the care of cancer patients. The first cancer patient was treated with CAR T-cell therapy in 2010 and the treatment ultimately led to the 2017 FDA approval of tisagenlecleucel (Kymriah) for pediatric acute lymphoblastic leukemia (ALL). A year later tisagenlecleucel gained approval for adults with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

Adverse events associated with this therapy are significant and include cytokine release syndrome (CRS) and neurologic toxicity.

CRS occurs after infusion and may include high fever, hypotension, and other serious hemodynamic changes. Fever occurs as tumor cells are being killed, and larger tumor volumes can yield higher fevers. CRS can be managed with agents that block the effects of interleukin-6, like tocilizumab (Actemra), and/or corticosteroids.

Neurotoxicity from CAR-T is now described as immune effector cell-associated neurotoxicity syndrome, and is characterized by global encephalopathy, aphasia, seizures or seizure-like activity, obtundation, tremor, myoclonus, and hallucinations. It is almost always reversible.

In addition to tisagenlecleucel, another CAR T-cell product, axicabtagene ciloleucel (Yescarta) is approved for certain types of non-Hodgkin's lymphoma. These therapies can only be administered by authorized clinicians.

If patients are considered to be candidates for CAR T-cell therapy, they have T cells harvested via leukapheresis. They undergo engineering so that they express CARs on their surface, then are multiplied. This process is estimated to take 8 to 12 days. When ready, they are infused back into the individual. Some patients will have cytoreductive chemotherapy prior to infusion. After infusion, patients remain in the hospital for close monitoring. The first month is critical in the process of recovery. Once injected into the patient, the CAR T cells expand from 1,000- to more than 10,000-fold. This expansion peaks at 10 to 14 days and coincides with the onset of CRS.

Results from ELIANA, a phase II trial of tisagenlecleucel in pediatric and young adult patients with CD19-positive relapsed or refractory B-cell ALL, demonstrated an overall remission rate of 81% at 3 months. Moreover, rates of event-free survival and overall survival (OS) were 73% and 90%, respectively, at 6 months and 50% and 76% at 1 year. CRS occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care. Long-term follow-up from the trial showed that two-thirds of those who attained complete responses remained in remission at 18 months.

In the JULIET trial, tisagenlecleucel was given to adult patients with relapsed or refractory DLBCL who were ineligible for or had disease progression after autologous stem cell transplant. Infusions were given to 93 patients and the therapy yielded an overall response rate of 52%, with complete responses in 40% and partial responses in 12%. At 12 months after initial response, the rate of relapse-free survival was 65%, and nearly 80% in those who achieved a complete response. The most common grade 3/4 adverse events of special interest included CRS (22%), neurologic events (12%), cytopenias lasting more than 28 days (32%), infections (20%), and febrile neutropenia (14%). Three patients died from disease progression within 30 days after infusion.

In the ZUMA-1 trial, treatment with axicabtagene ciloleucel led to a response rate of 82% among 101 patients with refractory DLBCL, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma. In all, 54% had a complete response. With a median follow-up of 15.4 months, 42% of the patients had maintained their response, including 40% of complete responders. Half of the patients remained alive at 18 months. The most common adverse events of grade 3 or higher were neutropenia in 78%, anemia in 43%, and thrombocytopenia in 38%. Grade 3 or higher CRS and neurologic events occurred in 13% and 28%, respectively. Three patients died during treatment.

At the recent American Society of Hematology (ASH) annual meeting, data from the phase I LEGEND-2 trial was presented to much enthusiasm. LCAR-B38M, a newer CAR T-cell therapy, was given to 57 individuals with relapsed/refractory multiple myeloma, leading to a response rate of 88%, with complete responses in 74%. Median duration of response was 22 months, and the 18-month OS rate reached 68%.

There are multiple ongoing trials using the FDA-approved compounds in other settings. Additional therapies are under investigation, and next-generation "smarter" CAR-T products are being developed. Those that address multiple targets will be prioritized. Hopefully, manufacturing and production will also be streamlined.

'Off the Shelf' Cellular Therapy

Despite the excitement surrounding CAR-T therapies, there have been concerns as well. These are patient-specific, personalized therapies that require waiting periods while the product is created. With traditional CAR T-cell therapy, patients must be well enough for cell collection and remain clinically stable for approximately 1 month before cells can be made and re-infused. It is estimated that about one-third of patients enrolled in CAR-T trials never make it to infusion due to the severity of their illness. Patients must also have an adequate supply of T cells to start with.

The nature of this personalized therapy means that there is a lot of work involved, along with the potential for human error. Associated costs are also very high, with estimates for the currently available products ranging from $370,000 to just shy of $500,000. This excludes costs of administration and costs related to prolonged hospitalizations due to adverse events.

Given the challenges of CAR-T therapy, clinical investigators are working to create a next generation of cellular therapies known as "off-the-shelf" treatments that can originate via a healthy donor's cells, and then be mass-produced and used for multiple patients -- so-called universal CAR T cells.

Multiple collaborators have active open-label, single-arm phase I trials for an off-the-shelf allogeneic CAR-T product called UCART19.

At ASH 2018, pooled data on 21 patients treated with UCART19 in two phase I trials -- PALL and CALM -- were presented. Of 17 patients who also received fludarabine/cyclophosphamide and an anti-CD52 monoclonal antibody, 82% achieved complete remission. In four patients who only received UCART19 and fludarabine/cyclophosphamide, no responses were observed and there was minimal UCART19 expansion. Safety was encouraging, as only two cases of low-grade graft-versus-host disease were seen, and neurotoxicity and CRS were as expected and manageable.

More recently, data from a large phase I study presented at the ASH 2019 meeting showed that 46% of 191 patients with relapsed, difficult-to-treat non-Hodgkin's lymphoma responded to mosunetuzumab, an investigational bispecific antibody. This included patients who were resistant or refractory to approved CAR T-cell therapies. The new agent, which targets CD3 and CD20, induced objective responses in 37% of patients with aggressive lymphomas and in 63% of those with indolent forms of the disease. In a subgroup of 18 patients with prior CAR-T exposure, seven responded to mosunetuzumab.

Advantages of such "off-the-shelf" therapies include their increased availability, that they eliminate the need for patients to have leukapheresis and the waiting period involved, and they are likely to be less expensive in comparison to traditional CAR-T.

We will likely witness an explosion of these products over the next few years.

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Region 3: Immune and Cellular Tx, Part II - MedPage Today