TCR-CAR+ iPSC-derived CD8 T Cells Induced Complete and Durable Responses In Vivo in Systemic Leukemia Model

Cell-surface Markers, Gene Transcription Profile, and In Vivo Anti-tumor Activity of TCR-CAR+ iPSC-derived CD8 T Cells Compared Favorably with Healthy-donor Peripheral Blood CAR T Cells

Phase 1 Study Ongoing of First-ever iPSC-derived T-cell Product Candidate FT819 for Off-the-shelf Treatment of Patients with Relapsed / Refractory B-cell Malignancies

SAN DIEGO, Aug. 09, 2022 (GLOBE NEWSWIRE) -- Fate Therapeutics, Inc. ( FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for patients with cancer, today announced the publication of preclinical study results demonstrating the successful generation, durable anti-tumor response, and functional persistence of TCR-CAR+ iPSC-derived CD8 T cells from induced pluripotent stem cells (iPSCs). The CD8 T cells were derived from a single engineered iPSC integrating a novel chimeric antigen receptor (CAR) transgene into the T-cell receptor alpha constant (TRAC) locus, ensuring complete bi-allelic disruption of T-cell receptor (TCR) expression and promoting uniform CAR expression. The discoveries were made under a multi-year research collaboration between the Company and Memorial Sloan Kettering Cancer Center (MSK) led by Michel Sadelain, M.D., Ph.D., Director, Center for Cell Engineering and Head, Gene Expression and Gene Transfer Laboratory, and were published this week in Nature Biomedical Engineering.

Scientists have previously differentiated induced pluripotent stem cells to form CAR T cells, however, it was observed that premature TCR or constitutive CAR expression resulted in the derivation of innate-like T cells that do not acquire the phenotype nor exhibit the function of conventional CD8 T cells, said Dr. Sadelain. Our published findings are the first to show the generation of iPSC-derived CD8 CAR T cells lacking a TCR, where timed and calibrated expression of the CAR in place of the TCR successfully drove T-cell maturation and promoted the acquisition of a transcriptional and functional profile more closely resembling that of natural CD8 T cells.

The mass production of TCR-CAR+ CD8 T cells from master engineered iPSC lines is a promising approach for development of off-the-shelf, cell-based cancer immunotherapies. Through a systematic assessment of factors that affect T-cell lineage commitment and induce adaptive T-cell formation, the researchers discovered that integrating the CAR construct into the TRAC locus delayed its expression and drove T-cell lineage commitment, and that regulation of CAR signaling strength promoted the generation of CD4+CD8+ double-positive cells mimicking thymic development in the absence of a TCR. Subsequent stimulation of the CAR matured the double-positive population into single-positive CD8 T cells with a phenotype highly correlated with peripheral blood CD8 effector T cells and distinct from T cells and natural killer cells. Preclinical studies showed that iPSC-derived TCR-CAR+ CD8 T cells were able to repeatedly lyse tumor cells in vitro and durably control leukemia in vivo, with persistence in the bone marrow, spleen, and blood, in a systemic NALM6 leukemia model.

These published findings continue to support our unique ability to generate TCR-CAR+ CD8 T cells from master engineered iPSC lines that exhibit a phenotypic profile and anti-tumor activity comparable to healthy donor-derived peripheral blood CAR T cells in preclinical model systems, said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics. We believe our off-the-shelf, iPSC-derived CAR T cell programs overcome the numerous challenges associated with the manufacture, consistency, and reach of autologous and allogeneic CAR T cells, and we look forward to sharing initial clinical data from our landmark Phase 1 study of FT819 later this year.

The Company is conducting a multicenter Phase 1 study of FT819, the first T-cell therapy manufactured from a clonal master iPSC line to undergo clinical investigation. The product candidates clonal engineered master iPSC line is created from a single iPSC that has a novel CD19-targeted 1XX CAR construct integrated into the TRAC locus, ensuring complete bi-allelic disruption of TCR expression to prevent graft-versus-host disease and promoting uniform CAR expression for enhanced anti-tumor activity. Dose escalation is currently ongoing in single-dose and multi-dose escalation cohorts for relapsed / refractory B-cell malignancies.

Pursuant to a license agreement with MSK, Fate Therapeutics has an exclusive license for all human therapeutic use to U.S. Patent No. 10,370,452, which covers compositions and uses of effector T cells expressing a CAR, where such T cells are derived from a pluripotent stem cell including an iPSC. In addition to the patent rights licensed from MSK, the Company owns an extensive intellectual property portfolio that broadly covers compositions and methods for the genome editing of iPSCs using CRISPR and other nucleases, including the use of CRISPR to insert a CAR in the TRAC locus for endogenous transcriptional control.

Fate Therapeutics has licensed intellectual property from MSK on which Dr. Sadelain is an inventor. As a result of the licensing arrangement, MSK has financial interests related to Fate Therapeutics.

About Fate Therapeutics iPSC Product PlatformThe Companys proprietary induced pluripotent stem cell (iPSC) product platform enables mass production of off-the-shelf, engineered, homogeneous cell products that are designed to be administered with multiple doses to deliver more effective pharmacologic activity, including in combination with other cancer treatments. Human iPSCs possess the unique dual properties of unlimited self-renewal and differentiation potential into all cell types of the body. The Companys first-of-kind approach involves engineering human iPSCs in a one-time genetic modification event and selecting a single engineered iPSC for maintenance as a clonal master iPSC line. Analogous to master cell lines used to manufacture biopharmaceutical drug products such as monoclonal antibodies, clonal master iPSC lines are a renewable source for manufacturing cell therapy products which are well-defined and uniform in composition, can be mass produced at significant scale in a cost-effective manner, and can be delivered off-the-shelf for patient treatment. As a result, the Companys platform is uniquely designed to overcome numerous limitations associated with the production of cell therapies using patient- or donor-sourced cells, which is logistically complex and expensive and is subject to batch-to-batch and cell-to-cell variability that can affect clinical safety and efficacy. Fate Therapeutics iPSC product platform is supported by an intellectual property portfolio of over 350 issued patents and 150 pending patent applications.

About FT819FT819 is an investigational, universal, off-the-shelf, T-cell receptor (TCR)-less CD19 chimeric antigen receptor (CAR) T-cell cancer immunotherapy derived from a clonal master induced pluripotent stem cell (iPSC) line, which is engineered with the following features designed to improve the safety and efficacy of CAR19 T-cell therapy: a novel 1XX CAR signaling domain, which has been shown to extend T-cell effector function without eliciting exhaustion; integration of the CAR19 transgene directly into the T-cell receptor alpha constant (TRAC) locus, which has been shown to promote uniform CAR19 expression and enhanced T-cell potency; and complete bi-allelic disruption of TCR expression for the prevention of graft-versus-host disease. FT819 demonstrated antigen-specific cytolytic activity in vitro against CD19-expressing leukemia and lymphoma cell lines comparable to that of primary CAR T cells, and persisted and maintained tumor clearance in the bone marrow in an in vivo disseminated xenograft model of lymphoblastic leukemia. FT819 is being investigated in a multicenter Phase 1 clinical trial for the treatment of relapsed / refractory B-cell malignancies, including B-cell lymphoma, chronic lymphocytic leukemia, and acute lymphoblastic leukemia (NCT04629729).

About Fate Therapeutics, Inc.Fate Therapeutics is a clinical-stage biopharmaceutical company dedicated to the development of first-in-class cellular immunotherapies for patients with cancer. The Company has established a leadership position in the clinical development and manufacture of universal, off-the-shelf cell products using its proprietary induced pluripotent stem cell (iPSC) product platform. The Companys immuno-oncology pipeline includes off-the-shelf, iPSC-derived natural killer (NK) cell and T-cell product candidates, which are designed to synergize with well-established cancer therapies, including immune checkpoint inhibitors and monoclonal antibodies, and to target tumor-associated antigens using chimeric antigen receptors (CARs). Fate Therapeutics is headquartered in San Diego, CA. For more information, please visit http://www.fatetherapeutics.com.

Forward-Looking StatementsThis release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995 including statements regarding the advancement of and plans related to the Company's product candidates, clinical studies and preclinical research and development programs, the Companys progress, plans and timelines for the manufacture and clinical investigation of its product candidates, the Companys initiation and continuation of enrollment in its clinical trials including additional dose cohorts in ongoing clinical trials of its product candidates, the therapeutic and market potential of the Companys product candidates, and the Companys clinical development strategy, including for its product candidate FT819. These and any other forward-looking statements in this release are based on management's current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to, the risk that the Companys product candidates may not demonstrate the requisite safety or efficacy to warrant further development or to achieve regulatory approval, the risk that results observed in prior studies of the Companys product candidates, including preclinical studies and clinical trials, will not be observed in ongoing or future studies involving these product candidates, the risk of a delay or difficulties in the manufacturing of the Companys product candidates or in the initiation and conduct of, or enrollment of patients in, any clinical trials, the risk that the Company may cease or delay preclinical or clinical development of any of its product candidates for a variety of reasons (including requirements that may be imposed by regulatory authorities on the initiation or conduct of clinical trials, changes in the therapeutic, regulatory, or competitive landscape for which the Companys product candidates are being developed, the amount and type of data to be generated or otherwise to support regulatory approval, difficulties or delays in patient enrollment and continuation in the Companys ongoing and planned clinical trials, difficulties in manufacturing or supplying the Companys product candidates for clinical testing, and any adverse events or other negative results that may be observed during preclinical or clinical development), the risk that results observed in preclinical studies of FT819 may not be replicated in ongoing or future clinical trials, and the risk that FT819 may not produce therapeutic benefits or may cause other unanticipated adverse effects. For a discussion of other risks and uncertainties, and other important factors, any of which could cause the Companys actual results to differ from those contained in the forward-looking statements, see the risks and uncertainties detailed in the Companys periodic filings with the Securities and Exchange Commission, including but not limited to the Companys most recently filed periodic report, and from time to time in the Companys press releases and other investor communications. Fate Therapeutics is providing the information in this release as of this date and does not undertake any obligation to update any forward-looking statements contained in this release as a result of new information, future events or otherwise.

Contact:Christina TartagliaStern Investor Relations, Inc.212.362.1200[emailprotected]

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Fate Therapeutics Announces Preclinical Publication Highlighting Derivation of CD8 T Cells from TCR-CAR+ Induced Pluripotent Stem Cells -...

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HAEMOGLOBIN IS a protein in your red blood cells. Your red blood cells carry oxygen throughout your body. If you have a condition that affects your bodys ability to make red blood cells, your haemoglobin levels may drop. Low haemoglobin levels may be a symptom of several conditions, including different kinds of anaemia and cancer.

If a disease or condition affects your bodys ability to produce red blood cells, your haemoglobin levels may drop. When your haemoglobin level is low, it means your body is not getting enough oxygen, making you feel very tired and weak.

Normal haemoglobin levels are different for men and women. For men, a normal level ranges between 14.0 grams per decilitre (gm/dL) and 17.5 gm/dL. For women, a normal level ranges between 12.3 gm/dL and 15.3 gm/dL. A severe low-haemoglobin level for men is 13.5 gm/dL or lower. For women, a severe low haemoglobin level is 12 gm/dL.

Your doctor diagnoses low haemoglobin by taking samples of your blood and measuring the amount of haemoglobin in it. This is a haemoglobin test. They may also analyse different types of haemoglobin in your red blood cells, or haemoglobin electrophoresis.

Several factors affect haemoglobin levels and the following situations may be among them:

Your body produces red blood cells and white blood cells in your bone marrow. Sometimes, conditions and diseases affect your bone marrows ability to produce or support enough red blood cells.

Your body produces enough red blood cells, but the cells are dying faster than your body can replace them.

You are losing blood from injury or illness. You lose iron any time you lose blood. Sometimes, women have low haemoglobin levels when they have their periods. You may also lose blood if you have internal bleeding, such as a bleeding ulcer.

Your body cannot absorb iron, which affects your bodys ability to develop red blood cells.

You are not getting enough essential nutrients like iron and vitamins B12 and B9.

Your bone marrow produces red blood cells. Diseases, conditions and other factors that affect red blood cell production include:

Lymphoma: This is a term for cancers in your lymphatic system. If you have lymphoma cells in your bone marrow, those cells can crowd out red blood cells, reducing the number of red blood cells.

Leukaemia: This is cancer of your blood and bone marrow. Leukaemia cells in your bone marrow can limit the number of red blood cells your bone marrow produces.

Anaemia: There are many kinds of anaemias involving low-haemoglobin levels. For example, if you have aplastic anaemia, the stem cells in your bone marrow dont create enough blood cells. In pernicious anaemia, an autoimmune disorder keeps your body from absorbing vitamin B12. Without enough B12, your body produces fewer red blood cells.

Multiple Myeloma: This causes your body to develop abnormal plasma cells that may displace red blood cells.

Chronic Kidney Disease: Your kidneys dont produce the hormone that signals to your bone marrow to make red blood cells. Chronic kidney disease affects this process.

Antiretroviral medications: These medications treat certain viruses. Sometimes these medications damage your bone marrow, affecting its ability to make enough red blood cells.

Chemotherapy: Chemotherapy may affect bone marrow cells, reducing the number of red blood cells your bone marrow produces.

Doctors treat low haemoglobin by diagnosing the underlying cause. For example, if your haemoglobin levels are low, your healthcare provider may do tests that reveal you have iron-deficiency anaemia. If that is your situation, they will treat your anaemia with supplements. They may recommend that you try to follow an iron-rich diet. In most cases, treating the underlying cause of anaemia will bring the haemoglobin level up.

Many things can cause low haemoglobin, and most of the time you cannot manage low haemoglobin on your own. But eating a vitamin-rich diet can help maintain your red blood cells. Generally, a balanced diet with a focus on important nutrients is the best way to maintain healthy red blood cells and haemoglobin.

keisha.hill@gleanerjm.comSOURCE: Centres for Disease Control and Prevention

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Factors that affect haemoglobin levels and how to detect when it's low - Jamaica Gleaner

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The media continues the one-handed count of patients that seem to be cured of HIV as a man who has lived with the disease since the 1980s has been in remission for 17 months.

The story is always the samethey seem to be cured, and they get a cool nicknamein this case the City of Hope Patient, after Duarte, California, where he was treated.

The difference in this case was the treatmenta bone marrow transplant to treat blood cancer leukemia from a donor who was naturally resistant to the virus.

The most remarkable difference however, is that he is only patient cured of HIV by coincidence.

The man had developed leukemia, and took the bone marrow transplant for that reason. As it happened, the donor was resistant to HIV, and taught the mans body to create an immune response against the virus.

RELATED: Worlds Second Person Cured of HIV: 40-Year-old Man is Confirmed to Be 30 Months Virus-Free

This is also the first one who got it during the epidemic of HIV/AIDS that took so many lives.

When I was diagnosed with HIV in 1988, like many others, I thought it was a death sentence, said the City of Hope Patient. I never thought I would live to see the day that I no longer have HIV.

SIMILAR: Two Patients Make History After Essentially Being Cured of HIV Using Stem Cell Transplant

So far, only three people have been seemingly cured of human immunodeficiency virus (HIV) which weakens the bodys immune system and leads to the more severe AIDS (autoimmune deficiency syndrome) which can be lethal.

The man no longer takes antiretroviral drugs, the only treatment for HIV. A bone marrow transplant is not a likely future cure, do to it being a tricky and side-effectual procedure.

Nevertheless, all cure cases have been those where a patient is given a transplant of some kind, mostly stem cells, that contain the very rarely occurring natural immunity to the virus.

The case was reported at the AIDS 2022 conference in Montreal, Canada.

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Fourth Patient Seemingly Cured of HIV Through Wild Coincidence - Good News Network

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IrelandUruguay, Eastern Republic ofUzbekistanVanuatuVenezuela, Bolivarian Republic ofViet Nam, Socialist Republic ofWallis and Futuna IslandsWestern SaharaYemenZambia, Republic ofZimbabwe

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BUDDY SCOTT: Love stems from the Father | Brazos Living | thefacts.com - Brazosport Facts

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MANY people suffer with back pain, whether that's from poor posture or a sporting injury.

Teenager Daniel Greer had been struggling with this - as well as neck pain.

2

2

But rather than an injury or pull - a blood test confirmed a shocking diagnosis.

The 14-year-old from Northern Ireland was told he had acute myeloid leukaemia two months ago.

Now his family are racing to find a stem cell donor - as this is his only chance of survival.

Since his diagnosis, the music fanatic has been staying at the Royal Belfast Hospital for Sick Children and is being treated with aggressive chemotherapy.

Doctors say that a stem cell transplant will help repair his immune system - but only one in four people will find a match within their own family.

His older brother James, sadly isn't a match so Daniel will need a transplant from an unrelated donor.

Mum, Anne, is now speaking out in the hopes of getting more people to sign up to the stem cell register - with the possibility of finding her son a donor.

She said: "Daniel is an amazing, bright young man who lights up any room he walks into.

"His wicked sense of humour keeps our spirits up, even now while hes in hospital receiving chemotherapy.

"I know hes really proud that his story is inspiring people to sign up to the stem cell register.

"Those people will potentially help him, as well as many other people around the world who desperately need a stem cell transplant like Daniel."

When it comes to the stem cell register, young men make up just 18 per cent of those on it, blood cancer charity Anthony Nolan states.

However, this demographic also makes up more than half of all stem cell transplants for blood cancer and blood disorder patients.

Now the charity is helping with an international appeal to get Daniel a donor, dubbed the DoItForDaniel campaign.

Daniel, lives in Newry and so far local pharmacies have got behind the campaign - urging people to sign up to help save the lives of others.

What is leukaemia?

Leukaemia is a type of blood cancer that affects cells in bone marrow and attacks the immune system.

In most cases of leukaemia, there is no obvious cause. Little Azaylia had been diagnosed with Acute Myeloid Leukaemia (AML) , which is a rapidly progressive form of the illness.

Leukaemia is a cancer that leads to the body making too many abnormal white blood cells and means the body is less likely to be able to defend itself against infection.

These blood cells are not fully developed and are called leukaemia cells.

The disease is often classified as the type of cell affected (myeloid or lymphatic) and how it progresses (acute or chronic).

There are four main types of leukaemia.

Acute Lymphocytic Leukaemia (ALL)-A rapidly progressing form of the disease.More common in children.

Acute Myeloid Leukaemia (AML) -Rapidly progressive. More common in adults.

Chronic Lymphocytic Leukaemia (CLL) -Slowly progressing form and more common in adults.

Chronic Myeloid Leukaemia (CML) -Progresses slowly and is more common in adults

There has also been an awareness-raising drive about stem cell donation at Belfast International Airport.

It's hoped that the drive will allow the keen mountain biker and rugby player to continue to do the things he enjoys most.

Anthony Nolan chief executive Henny Braund said that finding a matching donor would mean everything to Daniel and his family.

"We are committed to supporting Daniel as he waits for news of the donor who could save his life.

Last year over 1,300 people around the world with blood cancer or a blood disorder were given a second chance of life because of the wonderful people that are signed up to the Anthony Nolan register.

But too many people, like Daniel, are told there is no matching donor for them.

Signing up to the register is quick and simple, and we urge anyone who is in good general health, especially young men aged 16-30, to come forward and potentially save the life of someone like Daniel.

Anyone aged 16-30 can sign up online through the Anthony Nolan website.

DONATING STEM CELLS & SIGNING THE REGISTER

When you join a stem cell registry you are on standby to be matched and potentially save a life although many people are never called up.

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My little boy is fighting for his life after complaining of back pain you could save him... - The Sun

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Type 1 diabetes (T1D) is a chronic immune-mediated disease characterized by the destruction of pancreatic -cells, resulting in absolute insulin deficiency and hyperglycemia. It is primarily a disease of youth, accounting for approximately 85% of cases in people under the age of 20 and 5% to 10% of all diagnosed cases of diabetes [1,2]. Although the exact mechanisms are unknown, T1D is thought to develop through immune system activation against -cell antigens and the initiation of proinflammatory cytokine responses. Environmental factors, obesity, viral infections, and nutritional factors were found to play a role in the pathophysiology as well [3]. T1D predisposes to a number of comorbidities, such as obesity, chronic kidney disease, metabolic syndrome, coronary artery disease, and hypertension. Such predispositions may account for higher mortality rates, affecting up to one in 10 adult patients within a year of diagnosis [4]. In fact, diabetic nephropathy (DN) is said to account for up to 40% of end-stage renal disease (ESRD) cases worldwide. Cardiovascular events account for up to 70% of T1D deaths and are 10 times more common in diabetics than in non-diabetics [5]. Therefore, it is critical to focus on novel therapies that aim to reduce the risks of acute complications such as hypoglycemia and diabetic ketoacidosis (DKA) while avoiding long-term complications such as DN, neuropathy, and retinopathy [5].

Exogenous insulin is currently the most prevalent treatment for T1D. Although exogenous insulin administration may be life-saving, it is not a cure for the disease. If patients are unable to maintain tight glycemic control by strictly adhering to their insulin regimen, they will invariably develop severe secondary complications that may shorten their life span [6]. Exogenous insulin is not a viable substitute for normal pancreatic islet function, mainly due to the absence of accurate temporal glucose control over time [7]. The administration of insulin can also result in hypoglycemic episodes [6]. A cross-sectional study conducted in Mexico revealed that patients' fear of hypoglycemic episodes prevented them from complying with their insulin treatment plan [8].

Replacement of the defective insulin-producing cells (IPC) is yet another potential therapy for T1D. This is possible through transplantation of the pancreas. Since the first pancreatic transplant took place in 1966, over 50,000 such transplants have been performed worldwide. Patients with T1D who receive a pancreatic transplant were found to have a reduced risk of subsequent complications and a longer life expectancy [9]. However, since transplantation is a major surgical procedure, patients must be fit for surgery [6]. Transplants necessitate permanent immunosuppression, which may put patients at risk for a variety of infections. In addition, they are associated with a number of postoperative complications, such as pancreatitis, due to low tolerance to cold ischemia, bleeding, thrombosis, and anastomotic leakage, which may require relaparotomy and graft pancreatectomy in recipients [9].

An alternative to pancreatic transplantation that is both safe and effective is islet cell transplantation. Scharp et al. published the first case of allogeneic intraportal islet transplantation for T1D in 1990, which led to short-term insulin independence and paved the way for clinical islet transplantation [10]. Despite the fact that the immunosuppressive regimen reported from Edmonton, Canada, also known as the Edmonton protocol (the Edmonton protocol introduced significant adjustments to the transplantation procedure, including the use of an immunosuppressive regimen free of steroids and the transplanting of an average islet mass of 11,000 islet equivalents per kilogram) has achieved unprecedented success in islet transplantation in terms of insulin independence, a number of factors continue to influence the outcome of this minimally invasive procedure [11]. Islet cell transplantation can induce a rapid inflammatory reaction in the circulation, leading to the loss of the vast majority of transplanted islets. The use of large doses of immunosuppressants during transplantation compromises the long-term viability and function of the graft, and the need for long-term immunosuppressive medications after the transplant poses a risk of organ damage, malignancies, new infections, and new-onset T1D in patients [12]. The high cost of islet transplantation and the paucity of human cadaveric islets highlight the urgent need for innovative pancreatic islet transplantation procedures [7]. This is where stem cells (SCs) pose an important role.

SCs are a highly promising novel treatment for T1D due to their ability to differentiate into several cell types and their regenerative potential. SCs can be categorized into four basic groups based on their origin as shown in Figure 1.

Mesenchymal stem cells (MSCs), also called mesenchymal stromal cells, are non-hematopoietic, multipotent SCs. They can be extracted from a variety of sources, including bone marrow, liver, kidney, adipose tissue, urine, umbilical cord blood, umbilical tissue, Wharton's jelly, placenta, and even endometrial tissue (menstrual blood-derived endometrial stem cells - MenSC). Several surface markers, including CD73, CD90, and CD105, can be utilized to identify MSCs. Due to their ability to differentiate into numerous cell types, they can be used to repopulate damaged tissues [13,14]. MSCs have gained enormous popularity in the treatment of T1D because of their ability to regulate fibrosis and tissue regeneration, as well as their ability to modulate immunological function. In addition, they produce a variety of secretory molecules, such as cytokines and exosomes, which play an essential role in the treatment of T1D [15]. Studies on animals treated with MSCs have shown a significant reduction in hyperglycemia, as evaluated by a decrease in serum glucose and an increase in insulin and C-peptide levels. In addition, they were able to restore normal levels of lipid fractions. Using MSCs lowered the serum levels of both liver and kidney function markers in diabetic rats, demonstrating their hepato-renal protective benefits in T1D [16].

Several mechanisms have been discovered to play a role in the management of T1D by MSCs (Figure 2).

MSCs, such as bone marrow stromal cells, promote angiogenesis through the secretion of cytokines such as basic fibroblast growth factor and vascular endothelial growth factor (VEGF) [17]. In addition, they play a crucial role in immunomodulation by moving to areas of inflammation and modifying the phenotype of dendritic cells (DC), T cells, B cells, and natural killer cells. They downregulate proinflammatory cytokines and escape CD8+ T cell-mediated apoptosis, inhibit maturation of DC, while reducing T-lymphocyte proliferation via transforming growth factor-beta 1 (TGF-1), hepatocyte growth factor, and nitric oxide. By stimulating the production of regulatory T cells, TGF-1 plays a significant role in the immunomodulation of MSCs. MSCs have also been found to improve the function, survival, and graft outcome of neonatal porcine islets by increasing the expression of genes involved in the formation of endocrine cells, insulin, and platelet-derived growth factor alpha (PDGFR-). PDGFR- suppresses Notch 1 signaling (Notch 1 downregulates transcription factors involved in the formation of endocrine cells and insulin), resulting in the maturation and development of islet cells [18]. Zhou et al. discovered that wild-type p53-induced phosphatase 1 (a serine/threonine phosphatase) regulates the immunomodulatory properties of MSCs via the expression of interferon-alpha and bone marrow stromal cell antigen 2, consequently playing an important role in the therapeutic effects of MSCs in T1D [19].

Even though studies have shown that MSCs are capable of reconfiguring the immune system, they must be rescued to some extent from immune-mediated destruction, indicating that immunomodulation will be necessary even if a viable MSCs therapy for T1D is produced [20]. When using -cells from an allogeneic stem cell source, an alloreactive response to donor antigens will be generated unless we obtain SCs from the patient's own cells. To circumvent this, researchers have investigated encapsulation strategies employing semipermeable immune barriers to provide immune shielding and prevent graft rejection [21]. Some studies have also demonstrated that the use of suicide genes together with stem cell transplants promotes functional immune reconstitution and thereby prevents graft-versus-host disease in patients [22].

It has been demonstrated that MSCs undergo apoptosis in the circulation of the host or in engrafted tissues following delivery to the patient's body, which plays a significant part in their therapeutic role in T1D. During the execution of apoptosis, apoptotic extracellular vesicles (apoEVs), formerly known as apoptotic bodies, have emerged as regulators of numerous biological processes, as opposed to being only debris. Specifically, apoEVs have been shown to regulate T cell and macrophage immunological function as well as stimulate tissue repair, including skin regeneration and vascular protection [23].

This game-changing discovery of MSCs in the treatment of T1D has propelled biological sciences to a new level of sophistication, allowing for the manipulation of cell fate and the cultivation of higher-order cellular structures. However, there is still a huge gap regarding its application in actual clinical practice.

We were only able to find 12 clinical trials on PubMed that evaluated the use of MSCs in the treatment of T1D. Ten of the 12 studies were undertaken in Asia, primarily in China and India. To date, the exact pathogenesis of T1D is not fully understood. Genetic factors have been found to play a role in the development of T1D, which may have affected the outcomes of previous clinical trials. Therefore, conducting multiple different studies worldwide would not only enable us to identify the effects of ethnicity and genetics on the response to MSC therapy in T1D patientsbut also help us to generalize the efficacy of MSCs to the entire population. In order to achieve the best outcomes while using medications to treat T1D, it is also crucial to perform additional research to more clearly identify the pathophysiology of T1D.

In the course of studying the patient selection criteria utilized in clinical trials, we made a fascinating discovery. We found that every clinical study had excluded patients with immunosuppression, viral illnesses such as hepatitis B and C, comorbidities including hematologic diseases, rheumatologic diseases, and kidney diseases, and pregnant patients, all of which could have influenced the results of the studies. Our present understanding of the action of apoEVs, as described by Fu et al., leads us to believe that in order for MSCs to undergo apoptosis, their recipients must be able to initiate apoptotic activity [23]. In order for this to occur, patients must have a particular number of cytotoxic T cells or natural killer cells; hence, patients who do not meet this criterion are unlikely to benefit from MSC delivery. To further elucidate the mechanisms of action of MSCs, it is essential to undertake additional studies with immunosuppressed patients in order to identify the optimal cohort of T1D patients for MSC therapy. In addition, further clinical research should be conducted to uncover the apoptotic signals that stimulate tissue regeneration and angiogenesis, as recognizing these signals would allow us to utilize a channel in parenchymal tissue to increase its regeneration capacity.

We also observed that the majority of trials exclusively enrolled patients with recent-onset T1D. A study conducted in Iran revealed that early transplantation of MSCs resulted in superior outcomes for T1D patients compared to late transplantation. This may be due to the honeymoon phase of diabetes, which may have obscured the effects of MSCs in these studies [24]. The honeymoon phase is the period during which a person with T1D appears to improve and may only require minimal amounts of insulin or experience normal or near-normal blood sugar levels without insulin. To extrapolate the results to a larger population and unmask the effects of the honeymoon period, it is necessary to conduct trials on patients with late-onset T1D.

To date, the exact mechanism by which MSCs contribute to the remission of T1D has not been identified; therefore, further research is required to get a better knowledge of mechanisms such as immunomodulation, homing, and paracrine signaling of MSCs. It is also vital to undertake studies to discover the appropriate number of MSCs, injection frequency, and optimal infusion route in order to maximize results. Cai et al. concluded that pancreatic arterial transfusion would assist in avoiding the first pass pulmonary effect of MSCs, hence lowering the sequestration of MSCs in the lungs and allowing for optimal results [25].

A few studies have used 3D microspheres to increase the proliferation capacity of MSCs with positive results. However, there is insufficient information available regarding the proliferation capacity, revascularization, efficiency of differentiation, and survival time of MSCs. Therefore, conducting studies to elucidate these aspects of MSC therapy is an urgent necessity. We would also be able to learn more about the graft's survival time and tumorigenic potential if we followed the patients for a longer period of time.

Patient-specific variables such as age, body mass index, lifestyle, socioeconomic status, level of activity, diet, autoimmune status, and drug interactions must be taken into consideration while conducting studies and analyzing data. In order to identify the ideal conditions necessary to create the desired quantities of MSCs to achieve remission of T1D, future research must also incorporate in-depth information regarding external factors that affect the viability of MSCs, such as storage conditions, plating density, and culture media.

In this article, we aim to discuss the role of MSCsderived from various tissues in the treatment of T1D, as well as their feasibility and limitations.

We present a summary of the extraction methods, advantages, limitations, and outcomes from several studies of MSCs derived from various types of tissues.

The majority of umbilical cord tissue-derived stem cells (UC-MSCs) are found in the subcortical endothelium of the umbilical cord, the perivascular area, and Wharton's jelly [26]. According to studies, roughly1 106UC-MSC can be extracted from a 20 cm human umbilical cord [27]. MSCs isolated from Wharton's jelly have been grown for over 80 population doublings without showing any signs of senescence, morphological alterations, an increase in growth rate, or a change in their ability to develop into neurons. Recent research has demonstrated that xenotransplantation of post-differentiated human UC-MSC without immunosuppressive therapy does not result in rejection [28]. This lack of immunogenicity may be attributable to the absence of major histocompatibility II and co-stimulatory molecules such as CD80 (B7-1), CD86 (B7-2), and CD40 [29]. Chao et al. successfully differentiated human UC-MSC into clusters of mature islet-like cells with insulin-producing capacity. In the islet cells, they detected an increase in insulin and other -cell-related genes, including Pdx1, Hlxb9, Nkx2.2, Nkx6.1, and Glut-2. Moreover, they discovered that hyperglycemia in diabetic rats was greatly under control after xenotransplantation of human pancreatic islet-like cell clusters [28]. Patients with newly diagnosed T1D who received repeated intravenous doses of allogeneic UC-MSC showed improved islet cell preservation and a significant rise in postprandial C-peptide levels. However, C-peptide levels did not alter significantly in patients with juvenile-onset T1D. The number of UC-MSC contributed more than other indicators to the prediction of clinical remission, bolstering the evidence of dose-dependent therapeutic efficacy. Therefore, appropriate doses and courses of MSC transplantation should be granted importance in future research [30].

UC-MSC can also be used to treat chronic complications of T1D, such as neuropathy, DN, and retinopathy [31]. Studies have shown that intraperitoneal injection of human UC-MSC can ameliorate renal injury in streptozotocin-induced diabetic mice.[32]. A mice study conducted in China demonstrated that the combination of human UC-MSC and resveratrol can better protect renal podocyte function and the resulting reduction in blood glucose levels and renal damage is superior to those obtained with insulin administration [33]. This suggests that the combination of resveratrol and human UC-MSC may be an innovative technique for treating T1D; however, additional research on humans is necessary to determine the effects of this combination treatment on the management of DN.Another investigation involving mice revealed that UC-MSC therapy restored erectile function by suppressing toll-like receptor 4, alleviating corpora cavernosa fibrosis, and boosting the production of VEGF and endothelial nitric oxide synthase [34]. Nonetheless, a significant advantage of UC-MSC is that they are a rich source of many SCs that can be easily manipulated [27]. They are collected at delivery by clamping and severing the umbilical cord. There are no ethical concerns regarding the use of UC-MSC because the collecting process is non-invasive and retains material that would otherwise be discarded as waste.

Adipose tissue-derived mesenchymal stem cells (ADSCs) are a group of cells that arise from the mesoderm during embryonic development. Amongst several types, subcutaneous adipose tissue seems to be the most clinically relevant source, being available in abundance for harvest, and its isolation only slightly invasive [35,36].

While two major kinds of adipose tissue (white and brown) have been isolated and studied, we focus on white adipose, which produces ADSCs, as brown adipocytes have not yet demonstrated an association with insulin resistance. White adipose tissue expressing uncoupling protein 2 (an isoform of uncoupling protein 1in brown adipose) acts as a storage of excess energy in the form of triglycerides and is thus prone to causing obesity and abnormalities in metabolic pathways such as insulin resistance during hyperplasia [37].

The extracted cell group of interest consists of a putative stem cell population of fibroblast-like cells known as processed lipoaspirate (PLA), found within the stromal compartments of adipose tissue [38]. Obtaining the sample requires lipoaspiration, and although the technique does not negatively affect the function of ADSCs, the vacuum process involved can cause damage to mature adipocytes [37]. Studies have shown that successfully extracted PLA can then differentiate in vitro into multiple cell lineages (including adipogenic, myogenic, chondrogenic, and osteogenic cells), thus providing another source of SCs with multi-germ-line potential instead of the traditional bone marrow-derived MSCs [38-41]. The discovery of the ability of ADSCs to efficiently differentiate into IPC has shed new light on the approach to T1D management [41].

ADSCs utilization can help avoid ethical barriers and tumorigenic complications that are increasingly encountered during stem cell isolation from embryos and induced pluripotent SCs [36]. Yet another advantage of ADSCs for their therapeutic application happens to be the relatively painless procedure and high yields in harvested cell numbers compared to bone marrow procurement [40]. These cells are devoid of human leukocyte antigen-DR expression and therefore have been successfully transplanted via intravenous, intraperitoneal, and renal capsule administration in mice without the need for immunosuppression [36,42].

Insulin replacement therapy with the help of co-transplantation of insulin-secreting ADSCs has been studied as an alternative to lifelong insulin therapy. As with multiple studies, no adverse effects were observed with ADSCs infusion, and in fact, an impressive absence of DKA episodes in all participants was seen [43]. A prospective study conducted in 2015 on 20 patients with T1D found better diabetic control (hemoglobin A1c levels) and sustained improvements in fasting blood sugar, postprandial blood sugar, hemoglobin A1c, and C-peptide levels with the transplantation of autologous insulin-secreting ADSCs [44]. Dantas et al. concluded that combination therapy with ADSCs and Vitamin D (daily cholecalciferol for six months) without immunosuppression was safe, demonstrated immunomodulatory effects, and may play a role in -cell preservation in patients with newly diagnosed T1D [45]. The significant functional and morphological improvements in islet cells as early as two months after transplantation of IPC clusters derived from ADSCs point to the promising nature of this therapeutic approach for achieving target normoglycemia [46,47]. A recent study conducted in 2022 discovered that systemic administration of ADSCs protects male non-obese diabetic (NOD) mice against diabetes induced by programmed death-1 and programmed death-ligand 1 (PD-1/PD-L1) inhibition. Multiple injections of neutralizing antibodies against mouse PD-L1 induce a significant infiltration of immune cells in the islets and a decrease in the -cell area and insulin content of the pancreas. Despite this, systemic ADSCinjection partially protected the pancreas from -cell loss and preserved insulin content, indicating therapeutic potential in T1D [15].

Apart from the therapeutic uses in T1D, the ADSCtherapy has also been shown to reduce adverse effects brought about by complications such as DN and ESRD [48,49]. Inactivation of nuclear factor kappa B pathways and downregulation of VEGF-A, amongst others, are the major mechanisms involved in ameliorating the pathological manifestations of mice with DN [50].

The problem remaining, however, is the inability to become totally free of exogenous insulin. Research suggests that a much larger dose of IPC may be required for a sustained cure of T1D using ADSCs [51]. Therefore, the need of the hour is to conduct further research, placing emphasis on ways to either enhance the production of insulin in IPC derived from ADSCs or alter cell signaling pathways to obtain a greater number of IPC from ADSCs.

Bone marrow-derived mesenchymal stem cells (BM-MSCs) are a type of adult stem cell that is abundant in bone marrow and has low immunogenicity [52]. Bone marrow stem cells are broadly categorized into hematopoietic stem cells and MSCs. These cells are sourced from the same individual, potentially minimizing rejection problems and making it a form of therapy for T1D [53]. BM-MSCs can differentiate into functionally competent -cells in vivo, and NOD mouse studies have shown the formation of normal T cell and B cell function, implying that allogeneic bone marrow transplant could prevent islet destruction and restore self-tolerance [54,55]. Because of their well-documented hypoimmunogenic and immunomodulatory properties, BM-MSCs are an appealing therapeutic option for T1D [56].

One study looked at T1D patients with DKA and found BM-MSCs to preserve -cell function in T1D patients, reducing levels of fasting and post-prandial C-peptide levels, with one patient achieving insulin independence for a period of three months [57].

BM-MSCs have been demonstrated to mitigate the effects of metabolic and hepato-renal abnormalities, enhance lipid profiles, and improve carbohydrate and glycemic management. Following an eight-week period of injections with BM-MSCs in diabetic rats, an improvement was observed in their lipid profiles compared to diabetic rats that were not treated with BM-MSCs [16]. In addition, BM-MSCs therapy has been demonstrated to ameliorate diabetes-related liver damage by boosting endogenous hepatocyte regenerative mechanisms and enhancing liver function [58].

BM-MSCs have also been shown to effectively treat comorbidities of T1D, such as DN, poor wound healing, and erectile dysfunction (ED). Nagaishi et al. investigated a novel approach of mixing BM-MSCs with umbilical cord extracts in Wharton's Jelly to enhance the therapeutic effect of ameliorating renal injury in T1D patients with DN. The study demonstrated morphological and functional improvements of diabetes-derived BM-MSC in vitro and a therapeutic impact on DN in vivo, suggesting that this may be beneficial not only for patients with DN but also for patients with other diabetic complications [59]. One study looked to address the problem of impaired epithelial wound healing in T1D patients and found that BM-MSCs promote corneal epithelial wound healing via tumor necrosis factor-inducible gene 6-dependent stem cell activation [60]. Another promising phase I pilot clinical trial found that treating ED in T1D patients with two consecutive intracavernous injections of autologous BM-MSC was safe and effective [61].

Currently, several potential therapeutic approaches are being postulated to approach this issue of T1D from a new viewpoint. Suicide gene therapy is a strategy with potential. This method involves the introduction of suicide-inducing transgenes into the body via BM-MSC. As a result, several processes will be induced, including the suppression of gene expression, the production of intracellular antibodies that block the essential pathways of cells, and the transgenic expression of caspases and deoxyribonucleases. Current clinical trials are examining strategies to restore damaged organs with the use of stem cells as the delivery mechanism [62].

The idea of transplanting BM-MSCs provides patients with hope. Particularly significant are autologous BM-MSC (which are easy to obtain and avoid graft rejection after transplantation) in contrast to allogeneic BM-MSC transplantations, which may result in graft rejection and be accompanied by complications [52]. For stem cell therapy to be most beneficial, early delivery of stem cells following a diagnosis of T1D is necessary compared to intervention at later stages [63].

Table 1compares the properties of MSCs derived from the bone marrow, umbilical cord, and adipose tissue.

Recent research has demonstrated that menstrual blood-derived endometrial stem cells (MenSCs) have therapeutic promise for the treatment of T1D due to their exceptionally high rates of proliferation, noninvasive collection method, and significant immunomodulatory activity. In T1D model mice, MenSC and UC-MSC transplantation resulted in a significant decrease in blood glucose and insulin levels, as well as an improvement in the morphology and function of the liver, kidneys, and spleen [14]. A 2021 study found that MenSCs expressed pancreatic -cell genes such as INSULIN, GLUT-2, and NGN-3 and had a greater capacity to develop into pancreatic cells [64].

Dental pulp-derived mesenchymal stem cells (DP-MSCs) are one of the unique MSCs proposed for the treatment of T1D. DP-MSCs are derived from exfoliated human deciduous teeth and have the properties of being easy to obtain with minimal donor injury. In a study by Mo et al. DP-MSCs revealed the ability to differentiate into pancreatic -cells; nevertheless, before proceeding with larger-scale investigations to firmly establish this approach, it is necessary to devise procedures for optimal -cell differentiation in-vivo [65].

An in-vivo study revealed that conjunctiva-derived mesenchymal stem cells (C-MSCs) efficiently differentiated into pancreatic islet stem cells in 2D cultures and 3D scaffolds under optimal induction conditions. C-MSCs have a strong proliferative capacity, a spindle shape, a high potential for clonogenic differentiation, and are widely available. However, larger in vitro studies are necessary before C-MSCs can be deemed an established treatment for T1D [64].

Table 2 lists all clinical trials that have utilized MSCs in the treatment of T1D and complications related to T1D (Table 2).

Our article relies on a survey of free full-text research journals over the past decade; consequently, it is possible that we have omitted pertinent information from paid full-text as well as research articles published prior to 2010.In addition, the scope of this study is confined to studies in the English language, so we may have overlooked papers published in other languages.

MSCs are postulated to act in T1D and numerous other disorders through diverse mechanisms. Among these are homing and immunomodulation. Our review revealed that MSCs not only effectively reduce fasting blood sugar, C-peptide, and hemoglobin A1c levels but are also capable of treating microvascular complications associated with T1D. However, the specific pathophysiology of T1D diabetes is still unknown, making it difficult to develop novel treatments. To achieve remission of T1D, we must also consider the effects of additional factors on the efficacy of MSCs, including patient-specific variables such as age, body mass index, lifestyle, socioeconomic status, level of activity, diet, autoimmune status, and drug interactions, as well as external factors such as storage conditions, plating density, and culture media. Therefore, it is urgent to conduct larger-scale studies.

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The Role of Mesenchymal Stem Cells in the Treatment of Type 1 Diabetes - Cureus

Bone Marrow Stem Cells Comments Off on The Role of Mesenchymal Stem Cells in the Treatment of Type 1 Diabetes – Cureus | August 2nd, 2022

CASE SUMMARY

A 54-year-oldwoman presented with Revised International Staging System stage II multiple myeloma, based on evaluations that showed a hemoglobin level of 7.0 g/dL, 2-microglobulin of 6 mg/dl, albumin 3.2 g/dL, calcium 11.3 mg/dL, lactate dehydrogenase of 200 U/L, and creatinine clearance of 45 mL/min. Bone marrow showed 22% clonal plasma cells. Serum kappa free light chains were 24 mg/dL. She had no cytogenetic abnormalities and an ECOG performance score of 1. A PET/CT scan showed multiple bone lesions in the vertebrae. She had no extramedullary disease. She was diagnosed with IgG-kappa myeloma and was considered transplant eligible.

Daratumumab (Darzalex), bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (Dara-VRd) induction therapy was initiated. She achieved a very good partial response (VGPR) post induction therapy. She underwent stem cell mobilization and 2 months later underwent autologous stem cell transplant (ASCT). Her post-ASCT response was a VGPR.

DISCUSSION QUESTIONS

CAITLIN COSTELLO, MD: This patient did get a quadruplet regimen with dara-VRd. She achieved a VGPR post-induction, had stem cells mobilized, underwent her transplant, and post-transplant her response is a VGPR. What would you do next?

THOMAS DEKKER, MD: Consolidation with CAR [chimeric antigen receptor] T-cell therapy.

COSTELLO: With CAR T cell, sure. Youre going for it; I like it. This patient is post-transplant, they have a VGPR. The GRIFFIN study [NCT02874742] would give these patients consolidation with dara-VRd.

PREETI CHAUDHARY, MD: I would not do CAR T-cell therapy.

COSTELLO: What would you do?

CHAUDHARY: In my opinion, in multiple myeloma, patients do a maximum of 11 months with CAR T-cell therapy. It has a good response, but I dont think thats sustainable.

COSTELLO: I appreciate throwing ideas out there. That is not something we have an option to do right now. Its an interesting option, and something we can talk about; but yes, I agree with you. I think for the meantime, short of trials that are looking at doing CAR T-cell therapyparticularly for those patients who have not had an adequate response to transplant or consolidation, or patients who relapse shortly after their transplantI think the standard of care as it stands now is doing consolidation or trying to find a maintenance regimen to get them to minimal residual disease [MRD] negativity.

With all that being said, what are we going to do now for these patients? Weve talked about what these transplant eligible patients are getting consolidation and maintenance; weve talked about maintenance approaches for these patients who get quadruplets, to put them on doublets. Seeing all those deep response rates, is anyone getting cold on transplants? If we are going to get 90% remission rates, does anyone reconsider the role of transplant here?

PAMELA MIEL, MD: I dont make that call, meaning I still send patients to the transplant doctors to see if theyre going to proceed with the transplant or not. But, if theyre transplant eligible, they get referred.

COSTELLO: As a transplanter, I thank you for that. We want to see these patients, make the decisions, have the discussion with the patients so we can look at their risk/benefit profile, and understand their responses to their current therapy. So, please still send them in their third cycle, if not earlier, so we can have those discussions and make plans.

There are a lot of maintenance regimens that are out there, and different things to choose from; a whole other conversation in and of itself. Lenalidomide is the mainstay where we have an overall survival benefit, where we dont have it in any other maintenance regimens.1 But it does allow for the option of continued doublets. I think we will soon see daratumumab and lenalidomide as a doublet get added on to that maintenance therapy once we have some of these randomized trials that are going on that show the continued benefit of patients to get daratumumab in the maintenance setting if they did not receive it in the up-front setting.

DISCUSSION QUESTION

How likely are you to change your practice with respect to management of transplant eligible newly diagnosed myeloma?

DEKKER: I already use quadruplet.

MILAN SHETH, MD: I feel that we still need a lot of long-term data to get a better sense of what it is that were achieving with the quadruplet therapy. Im still not convinced everybody needs quadruplet therapy. I think somebody else had already said that we know were going to get better responses because were using great drugs, but do we need to use everything up-front? I feel like theres still a lot of unanswered questions here.

MIEL: Ive been wanting to put patients on quadruplet treatment. I dont know if you know Nina Shah, MD, over at UC San Francisco, but Ive attended some of her talks, and shes pushing for the quadruplet treatment. The only thing that changed my mind was that when I spoke to the transplant doctor at UC San Diego, he said, If its not very high-risk disease, Id go with VRd [bortezomib, lenalidomide, and dexamethasone]. So, I put the patient on VRd. But I probably would want to put someone on dara-VRd, given the chance.

COSTELLO: Yes. I think that my takeaway from the data has been that we would, of course, love long-term data to come out, butwe have to wait a long time for it. While were waiting for some of these phase 3 studies to go on, which are happening now to look at real randomized data, to play out, I find that this is just too intriguing to not do quadruplets for everybody now.

Since [these data were presented at [the 2021 American Society of Hematology annual meeting], Ive transitioned just about everyone whos at least transplant eligible over to quadruplet regimens now.2 Any patients who are on the fence, where Im not sure if theyre going to be eligible for transplant, I still will try and give them the benefit of a quadruplet regimen, and very quickly drop the bortezomib if I get worried about them, and end up with dara-Vd [daratumumab, lenalidomide, dexamethasone]. But I think these MRD negativity rates are just too good, and if that is going to be the true surrogate end point that were all aiming for, dara-VRd has been my go-to for the last 6-plus months or so for these patients, until someone tells me otherwise.

References

1. Ho M, Zanwar S, Kapoor P, et al. The effect of duration of lenalidomide maintenance and outcomes of different salvage regimens in patients with multiple myeloma (MM).Blood Cancer J. 2021;11(9):158. doi:10.1038/s41408-021-00548-7

2. Laubach JP, Kaufman JL, Sborov DW, et al. Daratumumab (DARA) plus lenalidomide, bortezomib, and dexamethasone (RVd) in patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): updated analysis of GRIFFIN after 24 months of maintenance. Blood. 2021;138(Suppl_1):79. doi:10.1182/blood-2021-149024

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Treating Multiple Myeloma Following Quadruplet Induction Therapy and ASCT - Targeted Oncology

Bone Marrow Stem Cells Comments Off on Treating Multiple Myeloma Following Quadruplet Induction Therapy and ASCT – Targeted Oncology | August 2nd, 2022

Researchers have revealed the cellular mysteries behind aging.

A new explanation for aging has been developed by researchers who have shown that genetic abnormalities that develop gradually over a lifetime cause substantial alterations in how blood is generated beyond the age of 70.

According to recent research, the drastic reduction in blood production beyond the age of 70 is likely caused by genetic alterations that steadily accumulate in blood stem cells throughout life.

Researchers from the Wellcome Sanger Institute, the Wellcome-MRC Cambridge Stem Cell Institute, and others have published a study that offers a new theory of aging in the journal Nature.

Somatic mutations, or alterations to the genetic code, occur in all human cells during the course of a lifetime. Aging is most likely caused by the accumulation of numerous sorts of damage to our cells over time, with one hypothesis proposing that the accumulation of somatic mutations causes cells to gradually lose functional reserve. However, it is still unknown how such slow-building molecular damage may result in the rapid decline in organ performance around the age of 70.

The Wellcome Sanger Institute, the Cambridge Stem Cell Institute, and collaborators examined the production of blood cells from the bone marrow in 10 people ranging in age from newborns to the elderly in order to better understand how the body ages.

3,579 blood stem cells had their whole genomes sequenced, allowing researchers to determine every somatic mutation present in each cell. Using this information, the team was able to create family trees of each persons blood stem cells, providing for the first time an impartial perspective of the connections between blood cells and how these ties develop over the course of a persons lifetime.

After the age of 70 years, the researchers discovered that these family trees underwent significant change. In adults under the age of 65, 20,000 to 200,000 stem cells contributed roughly equal amounts to the creation of blood cells. In contrast, blood production was exceedingly uneven in those above the age of 70.

In every elderly person investigated, a small number of enlarged stem cell clonesas few as 10 to 20contributed as much as half of the total blood output. Because of an uncommon class of somatic mutations known as driver mutations, these highly active stem cells have gradually increased in number during that persons life.

These findings led the team to propose a model in which age-associated changes in blood production come from somatic mutations causing selfish stem cells to dominate the bone marrow in the elderly. This model, with the steady introduction of driver mutations that cause the growth of functionally altered clones over decades, explains the dramatic and inevitable shift to reduced diversity of blood cell populations after the age of 70. Which clones become dominant varies from person to person, and so the model also explains the variation seen in disease risk and other characteristics in older adults. A second study, also published in Nature, explores how different individual driver mutations affect cell growth rates over time.

Dr. Emily Mitchell, Haematology Registrar at Addenbrookes Hospital, a Ph.D. student at the Wellcome Sanger Institute, and lead researcher on the study, said: Our findings show that the diversity of blood stem cells is lost in older age due to positive selection of faster-growing clones with driver mutations.

These clones outcompete the slower-growing ones. In many cases this increased fitness at the stem cell level likely comes at a cost their ability to produce functional mature blood cells is impaired, so explaining the observed age-related loss of function in the blood system.

Dr. Elisa Laurenti, Assistant Professor and Wellcome Royal Society Sir Henry Dale Fellow at the Wellcome-MRC Cambridge Stem Cell Institute at the University of Cambridge, and joint senior researcher on this study, said: Factors such as chronic inflammation, smoking, infection, and chemotherapy cause earlier growth of clones with cancer-driving mutations. We predict that these factors also bring forward the decline in blood stem cell diversity associated with aging. It is possible that there are factors that might slow this process down, too. We now have the exciting task of figuring out how these newly discovered mutations affect blood function in the elderly, so we can learn how to minimize disease risk and promote healthy aging.

Dr. Peter Campbell, Head of the Cancer, Ageing and Somatic Mutation Programme at the Wellcome Sanger Institute, and senior researcher on the study said: Weve shown, for the first time, how steadily accumulating mutations throughout life lead to a catastrophic and inevitable change in blood cell populations after the age of 70. What is super exciting about this model is that it may well apply to other organ systems too. We see these selfish clones with driver mutations expanding with age in many other tissues of the body we know this can increase cancer risk, but it could also be contributing to other functional changes associated with aging.

References: Clonal dynamics of haematopoiesis across the human lifespan by Emily Mitchell, Michael Spencer Chapman, Nicholas Williams, Kevin J. Dawson, Nicole Mende, Emily F. Calderbank, Hyunchul Jung, Thomas Mitchell, Tim H. H. Coorens, David H. Spencer, Heather Machado, Henry Lee-Six, Megan Davies, Daniel Hayler, Margarete A. Fabre, Krishnaa Mahbubani, Federico Abascal, Alex Cagan, George S. Vassiliou, Joanna Baxter, Inigo Martincorena, Michael R. Stratton, David G. Kent, Krishna Chatterjee, Kourosh Saeb Parsy, Anthony R. Green, Jyoti Nangalia, Elisa Laurenti, and Peter J. Campbell, 1 June 2022, Nature.DOI: 10.1038/s41586-022-04786-y

The longitudinal dynamics and natural history of clonal haematopoiesis by Margarete A. Fabre, Jos Guilherme de Almeida, Edoardo Fiorillo, Emily Mitchell, Aristi Damaskou, Justyna Rak, Valeria Orr, Michele Marongiu, Michael Spencer Chapman, M. S. Vijayabaskar, Joanna Baxter, Claire Hardy, Federico Abascal, Nicholas Williams, Jyoti Nangalia, Iigo Martincorena, Peter J. Campbell, Eoin F. McKinney, Francesco Cucca, Moritz Gerstung, and George S. Vassiliou, 1 June 2022, Nature.DOI: 10.1038/s41586-022-04785-z

The study was funded by Wellcome and the William B Harrison Foundation.

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Scientists Unlock the Secrets of Cellular Aging: What Happens After You Turn 70? - SciTechDaily

Bone Marrow Stem Cells Comments Off on Scientists Unlock the Secrets of Cellular Aging: What Happens After You Turn 70? – SciTechDaily | August 2nd, 2022

For those with cancer, the threat of serious illness from COVID-19 is often a major concern. Cancer treatments can weaken your bodys immune system, increasing your risk of a serious infection.

Immunotherapy is a type of cancer treatment that boosts and supports your immune system in responding against cancer. If you or a loved one is receiving immunotherapy treatment for cancer, you may have concerns about how the COVID vaccine may affect your immune system and your treatment.

This article will answer some common questions about immunotherapy cancer treatment and the COVID vaccines.

People with a weakened immune system due to cancer are at an increased risk for poor outcomes from COVID-19. No matter where you are in your treatment plan, vaccination can reduce your risk of developing severe COVID. Vaccination is important even for those with a robust immune system.

The National Comprehensive Cancer Network (NCCN) and the American Cancer Society recommend that people with cancer, including those receiving treatment, get vaccinated as soon as possible. NCCN notes a few exceptions regarding immediacy:

Since they weaken the immune system, some cancer treatments reduce but dont eliminate vaccine effectiveness. Even if youre getting one or more of these treatments, you will gain some protection from the vaccine. Treatments include:

Vaccination combined with protective measures, such as wearing a mask and avoiding large crowds, provides you with more protection from COVID than you would have without them. For that reason, experts strongly recommend vaccination for people with cancer or a history of cancer.

But check with your oncologist first about when you should get vaccinated. If you are currently receiving treatment for cancer, it may be best to wait until your immune system recovers from treatment. This will give you the best chance of mounting a strong immune response.

Both the Pfizer BioNTech and the Moderna mRNA vaccines are appropriate for use in people who take immunotherapy drugs. Neither vaccine is known to be better than the other for this population.

A 2021 study found that the Moderna vaccine was safe for people with solid tumors receiving chemotherapy, immunotherapy, or both. Their response to the vaccine was similar to those who did not have cancer. The groups also saw similar rates of side effects.

A separate 2021 study noted that people with solid tumors who had the Pfizer vaccine had similar antibody levels to those without cancer 6 months after vaccination. In the subgroup of people on immunotherapy, about 87% still had antibodies, compared to about 84% of the control group.

If you cannot get or do not want either of these vaccines, you can also get the Johnson & Johnson (Janssen) vaccine.

Having cancer or taking immunotherapy drugs does not increase the possibility of serious side effects, such as allergic reactions or myocarditis.

Swelling in the lymph nodes under the arm on the same side as the injection site is a potential side effect of vaccination. While temporary, this can be concerning for people with breast cancer and other cancers.

Tenderness and swollen lymph nodes caused by vaccination should subside within a few days to a few weeks. Let a healthcare professional know if the swelling increases or does not go away within this timeframe.

To date, researchers do not know definitively if immunotherapy drugs affect the effectiveness of COVID-19 vaccines, either positively or negatively.

Scientific articles from 2021 and 2022 suggest that checkpoint inhibitors could theoretically boost your immune response to the COVID-19 vaccine. But both articles also state that no study has demonstrated such an effect.

Some immunotherapy drugs, such as CAR T-cells, may weaken the immune system temporarily. This may make the vaccine less effective. Other types of immunotherapy drugs, such as monoclonal antibodies, should not have this effect.

People with compromised immune systems may find it difficult to generate a robust response to the vaccine, no matter what type of cancer treatment they receive. This may be particularly true for people with blood cancers. For that reason, dosing protocols for people who are immunocompromised and have cancer differ from those used for the general public.

To date, no data indicate that the COVID vaccine reduces the effectiveness of immunotherapy medication. But there may be a 17% to 48% risk of side effects due to an overstimulated immune response, according to research.

A case report published in May 2021 suggests the potential for cytokine release syndrome after COVID vaccination in patients taking certain immunotherapy drugs. The study authors state that more data is needed and still favor vaccination for people with cancer.

A 2021 study involving 134 people found no adverse effects from immunotherapy drugs after receiving the Pfizer vaccine. The studys authors also stressed the need for larger studies and more data, but supported vaccination for people receiving immunotherapy.

However, the impact of certain immunotherapy treatments on your immune system makes the timing of vaccination important. Talk with your oncologist about when you should schedule your vaccine.

People taking immunotherapy drugs should receive an additional primary dose of the vaccine if they have active cancer or are immunocompromised. You may fall into one of these categories if any of the following situations apply:

Yes. Getting COVID does not ensure you will not get it again. In fact, with ever-changing variants continually emerging, contracting the virus more than once has become commonplace.

If youre on cancer treatments that cause you to be immunocompromised, it is vital to get vaccinated, even if youve already had COVID. Talk with your oncologist about when you should get vaccinated after having COVID-19.

If you have cancer, you may be more likely to experience serious complications from COVID-19. Cancer treatments, including certain immunotherapy drugs, may affect your scheduling for vaccination. Talk with your oncologist about when you should schedule your vaccines and how many doses you should get.

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Immunotherapy and COVID Vaccine: Your Questions Answered - Healthline

Bone Marrow Stem Cells Comments Off on Immunotherapy and COVID Vaccine: Your Questions Answered – Healthline | August 2nd, 2022

Fibrosis is the thickening of various tissues caused by the deposition of fibrillar extracellular matrix (ECM) in tissues and organs as part of the bodys wound healing response to various forms of damage. When accompanied by chronic inflammation, fibrosis can go into overdrive and produce excess scar tissue that can no longer be degraded. This process causes many diseases in multiple organs, including lung fibrosis induced by smoking or asbestos, liver fibrosis induced by alcohol abuse, and heart fibrosis often following heart attacks. Fibrosis can also occur in the bone marrow, the spongy tissue inside some bones that houses blood-producing hematopoietic stem cells (HSCs) and can lead to scarring and the disruption of normal functions.

Chronic blood cancers known as myeloproliferative neoplasms (MPNs) are one example, in which patients can develop fibrotic bone marrow, or myelofibrosis, that disrupts the normal production of blood cells. Monocytes, a type of white blood cell belonging to the group of myeloid cells, are overproduced from HSCs in neoplasms and contribute to the inflammation in the bone marrow environment, or niche. However, how the fibrotic bone marrow niche itself impacts the function of monocytes and inflammation in the bone marrow was unknown.

Now, a collaborative team from Penn, Harvard, the Dana-Farber Cancer Institute (DFCI), and Brigham and Womens Hospital has created a programmable hydrogel-based in vitro model mimicking healthy and fibrotic human bone marrow. Combining this system with mouse in vivo models of myelofibrosis, the researchers demonstrated that monocytes decide whether to enter a pro-inflammatory state and go on to differentiate into inflammatory dendritic cells based on specific mechanical properties of the bone marrow niche with its densely packed ECM molecules. Importantly, the team found a drug that could tone down these pathological mechanical effects on monocytes, reducing their numbers as well as the numbers of inflammatory myeloid cells in mice with myelofibrosis. The findings are published in Nature Materials.

We found that stiff and more elastic slow-relaxing artificial ECMs induced immature monocytes to differentiate into monocytes with a pro-inflammatory program strongly resembling that of monocytes in myelofibrosis patients, and the monocytes to differentiate further into inflammatory dendritic cells, says co-first author Kyle Vining, who recently joined Penn. More viscous fast-relaxing artificial ECMs suppressed this myelofibrosis-like effect on monocytes. This opened up the possibility of a mechanical checkpoint that could be disrupted in myelofibrotic bone marrow and also may be at play in other fibrotic diseases. Vining will be appointed assistant professor of preventive and restorative sciences in the School of Dental Medicine and the Department of Materials Sciences in the School of Engineering and Applied Science, pending approval by Penn Dental Medicines personnel committees and the Provosts office.

Vining worked on the study as a postdoctoral fellow at Harvard in the lab of David Mooney. Our study shows that the differentiation state of monocytes, which are key players in the immune system, is highly regulated by mechanical changes in the ECM they encounter, says Mooney, who co-led the study with DFCI researcher Kai Wucherpfennig. Specifically, the ECMs viscoelasticity has been a historically under-appreciated aspect of its mechanical properties that we find correlates strongly between our in vitro and the in vivo models and human disease. It turns out that myelofibrosis is a mechano-related disease that could be treated by interfering with the mechanical signaling in bone marrow cells.

Mooney is also the Robert P. Pinkas Family Professor of Bioengineering at Harvard and leads the Wyss Institutes Immuno-Materials Platform. Wucherpfennig is director of DFCIs Center for Cancer Immunotherapy Research, professor of neurobiology at Brigham and Harvard Medical School, and an associate member of the Broad Institute of MIT and Harvard. Mooney, together with co-senior author F. Stephen Hodi, also heads the Immuno-engineering to Improve Immunotherapy (i3) Center, which aims to create new biomaterials-based approaches to enhance immune responses against tumors. The new study follows the Centers road map. Hodi is director of the Melanoma Center and The Center for Immuno-Oncology at DFCI and professor of medicine at Harvard Medical School.

Gleaning mechanical bone marrow failureThe mechanical properties of most biological materials are determined by their viscoelastic characteristics. Unlike purely elastic substances like a vibrating quartz, which store elastic energy when mechanically stressed and quickly recover to their original state once the stress is removed, slow-relaxing viscoelastic substances also have a viscous component. Like the viscosity of honey, this allows them to dissipate stress under mechanical strain by rapid stress relaxation. Viscous materials are thus fast-relaxing materials in contrast to slow-relaxing purely elastic materials.

The team developed an alginate-based hydrogel system that mimics the viscoelasticity of natural ECM and allowed them to tune the elasticity independent from other physical and biochemical properties. By tweaking the balance between elastic and viscous properties in these artificial ECMs, they could recapitulate the viscoelasticity of healthy and scarred fibrotic bone marrow, whose elasticity is increased by excess ECM fibers. Human monocytes placed into these artificial ECMs constantly push and pull at them and in turn respond to the materials mechanical characteristics.

Next, the team investigated how the mechanical characteristics of stiff and elastic hydrogels compared to those in actual bone marrow affected by myelofibrosis. They took advantage of a mouse model in which an activating mutation in a gene known as Jak2 causes MPN, pro-inflammatory signaling in the bone marrow, and development of myelofibrosis, similar to the disease process in human patients with MPN. When they investigated the mechanical properties of bone marrow in the animals femur bones, using a nanoindentation probe, the researchers measured a higher stiffness than in non-fibrotic bone marrow. Importantly, we found that the pathologic grading of myelofibrosis in the animal model was significantly correlated with changes in viscoelasticity, said co-first author Anna Marneth, who spearheaded the experiments in the mouse model as a postdoctoral fellow working with Ann Mullally, a principal investigator at Brigham and DFCI, and another senior author on the study.

Targeting dysregulated bone marrow mechanicsAn important question was whether monocytes response to the mechanical impact of the fibrotic bone marrow niche could be therapeutically targeted. The researchers focused on an isoform of the phosphoinositide 3-kinase (PI3K)-gamma protein, which is specifically expressed in monocytes and closely related immune cells. PI3K-gamma is known for regulating the assembly of a cell-stiffening filamentous cytoskeleton below the cell surface that expands in response to mechanical stress, which the team also observed in monocytes encountering a fibrotic ECM. When they added a drug that inhibits PI3K-gamma to stiff elastic artificial ECMs, it toned down their pro-inflammatory response and, when given as an oral treatment to myelofibrosis mice, significantly lowered the number of monocytes and dendritic cells in their bone marrow.

This research opens new avenues for modifying immune cell function in fibrotic diseases that are currently difficult to treat. The results are also highly relevant to human cancers with a highly fibrotic microenvironment, such as pancreatic cancer, says Wucherpfennig.

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This week, the White House held a summit on the future of Covid-19 vaccines that brought together scientists and vaccine manufacturers to discuss new vaccine technologies. Officials said that new vaccines are an urgent priority as US Covid-19 cases and hospitalizations are rising once again, vaccination rates are hitting a plateau, Covid-19 funding is running low, and the virus itself is continuing to mutate.

But in recent months, scientists have also learned that the immune cells that provide lasting protection known as memory B cells and T cells can keep the worst effects of the most recent versions of the virus at bay, even if they were trained to corral older strains of SARS-CoV-2. Vaccine researchers are expanding their focus from antibodies to these memory immune cells as the new discoveries open a path toward universal coronavirus vaccines.

Universal vaccines, however, are still a long way off possibly years drawing on approaches never used before. Thats a scientific challenge, said Anthony Fauci, chief medical adviser to the president, during the summit.

The good news is that far fewer people are dying from the disease compared to the wave of cases this past winter spurred by the omicron variant of SARS-CoV-2, the virus that causes Covid-19. The first round of Covid-19 vaccines is still holding death rates down to around 360 per day, according to the Centers for Disease Control and Prevention. Still, health officials want to do better.

While the vaccines are terrific, hundreds of Americans, thousands of people around the world are still dying every day, Ashish Jha, the White House Covid-19 response coordinator, said Tuesday. Building a new generation of vaccines will make an enormous difference to bringing this pandemic to an end.

The National Institutes of Health is already funding several research teams developing Covid-19 vaccines that elicit protection against many different versions of the virus, shield against future changes to the virus before they arise, and protect against other coronaviruses.

From there, health officials are aiming not just to develop vaccines that provide more durable protection against a wider array of threats, but also rethinking the vaccination strategy overall. With a better understanding of long-term immunity, more robust vaccines, and a comprehensive public health approach, health officials say they have a better shot at restoring normalcy.

Much of the discussion around vaccines and immunity to Covid-19 centers on antibodies, proteins produced by the immune system that attach to the virus. And indeed, they are important.

Antibodies that prevent the virus from causing an infection in the first place are called neutralizing antibodies. A high concentration of antibodies in the body that blocks SARS-CoV-2 is a key indicator of good protection against reinfection. Antibodies can also serve as a way to mark intruders so that other immune system cells can dispose of them.

But making large quantities of antibodies takes a lot of resources from the body, so their production tapers off with time after an infection or a vaccination. Another concern is that antibodies are very particular about where they attach to the virus. If the virus has a mutation at that attachment site called an epitope antibodies have a harder time recognizing the pathogen. Thats why some antibody-based treatments for Covid-19 are a lot less effective at stopping the omicron subvariants.

Fortunately, the immune system has other tools in its chest. Inside bone marrow lie stem cells that differentiate to become B cells and T cells. Together, they form the core of the adaptive immune system, which creates a tailored response to threats. After a virus invades a cell, it hijacks its machinery to make copies of itself. White blood cells known as cytotoxic T cells, a.k.a. killer T cells, can identify the wayward cell and make it self-destruct. This mechanism doesnt prevent infections, but it stops them from growing out of control.

Another type of T cell, called a helper T cell, acts as an on switch for B cells, which are the cells that manufacture antibodies. After an infection is extinguished, some T cells and B cells turn into memory cells that stick around in parts of the body, ready to rev up if a virus dares to show up again.

So far, the adaptive immune system seems to hold up pretty well. The first round of Covid-19 vaccines was targeted against the earliest versions of the virus, so plenty of vaccinated people have had breakthrough infections, especially from the newer variants. But only a tiny fraction of those immunized have fallen severely ill or have died.

That likely means that their immune systems couldnt keep the virus out entirely, but their immune cells were able to spool up once an infection took root.

Someones neutralizing antibodies may not be up to the task, but if they have the T cell response, that may make all the difference with severe disease, said Stephen Jameson, a professor of microbiology and immunology at the University of Minnesota.

In just the past year, many studies have borne out the significance of memory B cells and T cells for long-term Covid-19 immunity and answered critical questions about whether they can respond to new variants.

Researchers have found that lower levels of memory B cells were associated with a greater risk of breakthrough infections from the delta variant. On the other hand, B cells induced by Covid-19 vaccines could reactivate months out from the initial vaccine doses to churn out antibodies.

Similarly, scientists found that T cells generated by vaccines were able to recognize SARS-CoV-2 variants like omicron months later. These data provide reasons for optimism, as most vaccine-elicited T cell responses remain capable of recognizing all known SARS-CoV-2 variants, scientists wrote in a March paper in the journal Cell.

Another study showed that Covid-19 vaccines generated strong T cell memory that protected against the virus even without neutralizing antibodies. I think the immunological memory which is induced by vaccines is pretty good and is actually sustained, said Marulasiddappa Suresh, a professor of immunology at the University of Wisconsin-Madison who co-authored the study, published in the Proceedings of the National Academy of Sciences in May.

Whether this protection will hold up over the course of years remains to be seen. Experiences with past coronaviruses like MERS showed that antibodies to the virus can last for four years. Covid-19, however, is spreading at much higher levels and mutating more than MERS did during its initial outbreak. Future protection against the disease hinges on the immune system as well as how much the virus itself will change, and scientists are closely watching both.

Most vaccines to date are designed to counter one or a handful of versions of a given virus. They present the immune system with a target that allows it to prepare its defenses should the actual virus ever invade.

In the case of Covid-19, most vaccines coach the immune system to target the spike protein of the SARS-CoV-2 virus, which it uses to start the infection process. This helps the immune system generate strong neutralizing antibodies. But the spike protein is one of the fastest mutating parts of the virus, making it a moving target.

The fact that B cells and T cells have managed to hold off newer variants hints that it may be possible to target the virus in other ways. Rather than just making neutralizing antibodies that attach to the spike, the adaptive immune system could also produce non-neutralizing antibodies that bind to other regions of the virus that mutate very little, if at all. While these antibodies may not block an infection from taking root, they may be able to provide more durable protection against severe illness that holds up against future SARS-CoV-2 variants.

Another approach is to present the immune system with a variety of different potential mutations of a virus, allowing white blood cells to prepare a response to a spectrum of threats and fill in the blanks.

Universal vaccines have not been deployed before, so researchers are in uncharted territory, and the shots likely wont be ready ahead of a potential fall spike in Covid-19 cases. But developing such a vaccine could eventually reduce the need for boosters and give health officials a head start on countering future outbreaks.

In the meantime, US health officials are planning to distribute vaccines reformulated to target newer Covid-19 variants by September, but its not clear yet what the optimal strategy will be to deploy them given the wide range of immune protection across the population. Between infections and vaccinations, the majority of people in the country have had some exposure to the virus, granting some degree of protection. And since the adaptive immune response to Covid-19 seems to be robust in most people, it may not be necessary for everyone to get an additional shot.

One option is to seek out those with weaker immune systems for boosters. Researchers have now developed a rapid test to measure T cell responses to Covid-19 that could identify people who are more vulnerable to reinfections or breakthrough infections.

Though vaccines are absorbing the most severe consequences from Covid-19, infections are still proving disruptive. Covid-19 outbreaks are contributing to staffing shortages at hospitals, schools, and airlines, leading to delays and cancellations. And the more the virus spreads, the more opportunities it has to mutate in dangerous ways. Stopping this threat requires limiting infections, which in turn still demands measures like social distancing and wearing face masks.

So as good as the next generation of vaccines may prove to be, they are only one element of a comprehensive public health strategy for containing a disease.

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How long-term Covid-19 immunity paves the way for universal Covid-19 vaccines - Vox.com

Bone Marrow Stem Cells Comments Off on How long-term Covid-19 immunity paves the way for universal Covid-19 vaccines – Vox.com | August 2nd, 2022

Mesenchymal stem cell isolation and expansion

Bone marrow-derived MSCs were isolated from young (6 weeks) and old (1824 months) C57 black male mice using established techniques42,43 under a protocol approved by the Johns Hopkins University Animal Care and Use Committee. Briefly, immediately following euthanasia, whole bone marrow was flushed out from the bilateral tibias and femurs. After washing by centrifugation at 400g for 10min, cells were plated at 5 106 viable cells per ml. The culture was kept in humidified 5% CO2 incubator at 37C for 72h, when non-adherent cells were removed by changing the media.

All MSC preparations were evaluated using flow cytometry with PE or FITC-conjugated antibodies against murine Sca-1 (1:200; BioLegend 122507), CD31 (1:200; Fisher Scientific BDB554473), CD34 (1:100; eBioscience 14-0341-82), CD44 (1:100; BioLegend 103007), CD45 (1:100; BioLegend 103105), and IgG (1:100; BioLegend 400607) performed on BD LSRII (Becton Dickinson) using DIVA software. At least 10000 events were collected. FlowJo software was used to analyze and create the histograms.

Assessment for osteogenic and adipogenic differentiation was performed using established techniques43. Briefly, to induce osteogenic differentiation, old and young MSCs were seeded into 6-well plates at 1.3 104 cells/well. After 24h the media was replaced with osteogenic differentiation medium containing Iscoves medium supplemented with 100nM dexamethasone, 10mM beta-glycerophosphate, 50 M ascorbic acid, and 1% antibiotic/antimycotic. Cells were maintained in induction media with media changes every 2 days. After 14 days cells fixed in 10% formalin for 15min and calcium deposition was assessed using von Kossa staining. Calcium deposition was then quantified using a colorimetric calcium assay (Calcium CPC Liquicolour Kit StanBio, Boerne, TX) according to the manufacturers instructions. To induce adipogenic differentiation, old and young MSCs were seeded in 6-well plates at 2 105 cells/well. When confluent the media was replaced with adipogenic induction medium containing DMEM-HG, 10% FBS, 5% rabbit serum, 1uM dexamethasone, 10g/mL insulin, 200 M indomethacin, 500 M isobutylmethylxanthine (IBMX), and antibiotic/antimycotic for 3 days followed by exposure to followed by exposure to adipogenic maintenance medium (DMEM-HG, 10% FBS, insulin 10g/ml and P/S) for 3 days. After 3 cycles of induction and maintenance exposure cells were rinsed with PBS and fixed in 10% formalin for 10min. The cells were then stained with Oil Red O to assess for lipid droplets. After imaging Oil Red O extraction was performed using 100% isopropanol. Extract samples were transferred to a 96-well plate and absorbance readings were taken at 490nm to quantify extracted Oil Red O.

Confirmed MSCs were expanded in culture in media prepared by combining 490ml Medium 200 PRF (Gibco Invitrogen, Carlsbad, CA), a standard basal medium intended for culture of large vessel human endothelial cells, with 10ml Low Serum Growth Supplement (LSGS; Gibco Invitrogen). The final preparation contained 2% fetal bovine serum (FBS), 3ng/ml basic fibroblast growth factor (bFGF), 10ng/ml human epidermal growth factor, 10g/ml heparin, and 1g/ml hydrocortisone. Cells were incubated under standard conditions (5% CO2 and 37C). Expanded MSCs at low passage numbers (P2-P5) were used for the experiments. In the event frozen cells were used, they were thawed and grown for one passage prior to use in the experiments.

To prevent cell-cell interaction and assess only paracrine-mediated effects (i.e. those resulting from release of soluble factors), angiogenesis experiments were performed using bioreactor tubes (BT) constructed with CellMax semi-permeable polysulfone membrane tubing (Spectrum Labs, Rancho Dominguez, CA). These allowed the free diffusion of soluble proteins and other molecules released by the cells up to a 500kDa molecular weight cut-off, but not of the cells themselves. To load BTs, MSCs were trypsinized and suspended in Medium 200 PRF without LSGS supplementation (i.e. media devoid of stimulatory growth factors). MSCs were counted using a Scepter automated cell counter (Millipore, Billerica, MA), which had been previously standardized for accuracy. The desired number of MSCs was spun down and resuspended to a total volume of 100 ul that was injected into the BTs using a 0.5mL syringe. To compare paracrine-mediated angiogenesis by old and young MSCs, BTs were loaded with either 105 old or 105 young MSCs. Once cell injection was complete, the tubes were heat-sealed at both ends and the MSC-loaded tubes, fully submerged in media, were grown at standard culture conditions (37C, 5% CO2) for 7 days (Fig. 3a).

ELISA assays were performed to measure paracrine factor (PF) production by the MSCs contained within the BTs grown in culture. Tubes loaded with 2 105 MSCs were submerged in 5mL of alpha-MEM basal medium (Stemcell Technologies, Tukwila, WA) supplemented with 20% FBS (Gibco Invitrogen, Carlsbad, CA) in a 6-well plate. At day 7, conditioned media was collected from each well, spun down for 1min to pellet any debris, and then flash frozen at 80C. Conditioned media samples were assessed for the concentrations of vascular endothelial growth factor (VEGF), stromal derived factor-1 (SDF1) and insulin-like growth factor-1 (IGF1) by ELISA (Quantikine, R&D Systems, Minneapolis, MN) according to the manufacturers instructions.

BTs were removed at day 7 and placed in separate wells of a 6-well plate containing human umbilical vein endothelial cells (HUVECs)44. Briefly, 105 HUVECs (Gibco Invitrogen, Carlsbad, CA) suspended in Medium 200PRF were plated per well in Geltrex (Gibco Invitrogen) coated 6-well plates. Negative control wells received a bioreactor loaded with un-supplemented Medium 200PRF only (i.e. no cells). Positive control wells were plated with 105 HUVECs suspended in 1mL of Medium 200PRF supplemented with LSGS, which is known to induce HUVEC tubule formation. After 18h at standard culture conditions (37C, 5% CO2), the wells were imaged to allow quantitative analysis of the resultant HUVEC tubule network. Images were taken in the center of each well and in all four quadrants at pre-determined locations (5 pictures total), at 100x magnification. The total length of the tubule networks captured in the images of each well was measured using ImageJ software. To allow for comparisons between experiments, the total length of the tubule network in each well was normalized to the average length of the tubule network in the negative control wells, and reported as a normalized ratio.

To assess the effect of young MSC-generated PFs on PF-mediated angiogenesis by old MSCs, BTs were prepared as described above containing either 105 young or 105 old MSCs. Two BTs were placed together in a 6-well plate in 5mL MSC media and incubated for 7 days at standard culture conditions (Fig. 3b) using a BT containing old MSCs paired with either a separate BT with other old MSCs (control) or a separate BT with young MSCs. After 7 days the tubes were removed, washed with un-supplemented Medium 200 PRF, and then used separately in the HUVEC assay as described above. After the HUVEC assay was complete (18h) the BTs were placed in separate wells of 6-well plates and grown in culture for 7 additional days with collection of conditioned media for PF release.

Replicates of 105 old MSCs were cultured separately, or in co-culture with young MSCs, for 7 days using a 0.4m Transwell system in 6-well plates (Corning), which allow transfer of soluble paracrine factors released by the cells, but not of the cells themselves. Following RNA purification, library preparation, amplification, and Illumina sequencing, the open source Galaxy pipeline was used for data processing and analyses. After alignment of raw sequencing reads to the UCSC mm10 genome using HISAT2, transcript assembly, alignment quantification, count normalization, and differential expression analyses were conducted with StringTie, featureCounts, DESeq2, and Genesis. Quantitative PCR (KAPA SYBR FAST One-Step qRT-PCR, Wilmington, MA) was used to validate 24 transcripts identified by RNA sequencing. Target genes were selected based on their presence in significantly regulated pathways and quantified relative to 18S ribosomal RNA using the 2Ct method45.

To validate the results of the RNA sequencing and RT-PCR results, a functional autophagy assay was performed to assess relative autophagy between old, young, and rejuvenated old MSCs. Old, young and rejuvenated cells were cultured (or co-cultured, in the case of rejuvenated cells) for 7 days in 6-well plates (105 cells per well). On Day 8, cells were trypsinzed, counted and 104 cells were transferred to each well of a 96-well black plate with clear bottom and incubated for 6h. The Autophagy Assay Kit (Sigma Aldrich, St. Louis, MO) measures autophagy using a proprietary fluorescent autophagosome marker in a microplate reader (ex=360; em=520nm). Three separate experiments were performed in triplicate each for each condition. To account for possible differences introduced by counting cells, results for each cell type were normalized based on absorbance (450nm) of a Cell Counting Kit-8 (Dojindo Molecular Technologies, Inc. Rockville, MD).

Data are reported as mean standard error of the mean (SEM) unless otherwise indicated. Comparisons between groups for the HUVEC experiments were performed using the permutation test. For the PF ELISA data, groups were compared using the MannWhitney test. The autophagy assay and rt-PCR results were assessed using two-tailed t tests. For these experiments a p-value < 0.05 was deemed significant. In the RNA sequencing differential expression analysis, a false discovery rate (FDR) of <0.05 was considered significant.

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In short, stem cells initiate the production of new tissue cells, which can then replace their diseased counterparts.

Mesenchymal stem cells (MSCs) are adult stem cells found in many areas of the body such as bone marrow. The unique thing about these cells is their compatibility with a range of tissues such as bone, cartilage, muscle, or fat. MSCs respond to injury or disease by migrating to these damaged areas, where they restore tissue function by replacing the damaged cells.

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It has recently been shown that the success of MSCs relies on their ability to release cell signals their mechanism to initiate tissue regeneration. These signals are packaged into extracellular vehicles (EVs) which are essentially bubbles of information. These are released by MSCs and taken up by the injured or diseased tissue cells to kickstart their inbuilt process of regeneration.

Through funding from the Royal Society of Edinburgh, research has started into the development of artificial EVs as a viable alternative to cell therapy. These EVs will contain the key molecules released by stem cells when they are responding to injury cues in the body.

The power to induce tissue regeneration would provide a significant new tool in biomedical treatment, such as incorporating EVs into synthetic hydrogels within a wound dressing to encourage and accelerate healing.

Within the lab setting, we have been able to manipulate stem cell cultures to produce EVs with different signal make-ups, and accurately identify their properties.

Controlling and identifying the different make-ups contained in EV signals which in turn induce different cell responses is crucial if we want to operationalise their use in medicine.

We now aim to synthesise artificial vesicles, or bubbles, for different clinical problems, such as, for example, bubbles with potent wound-healing properties that would help our ability to use new artificial stem cell therapy.

The research is underway and it is showing promise that we may be able to harness the regenerative power of stem cells in the near future.

An artificial EV-based approach also has several advantages over stem cell-based therapies, such as having increased potency and greater consistency in treatment, and at a lower cost to carry out.

Both inside and on the surface of the body, we would have the ability to induce a process vital to medical treatment we work with every day and, in turn, open a whole new avenue of possibilities in biomedical science.

Dr Catherine Berry is a reader in the Centre for the Cellular Microenvironment at the University of Glasgow, and a recipient of the Royal Society of Edinburghs personal research fellowship in 2021. This article expresses her own views. The RSE is Scotland's national academy, bringing great minds together to contribute to the social, cultural and economic well-being of Scotland. Find out more at rse.org.uk and @RoyalSocEd.

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Stem cells: Could we gain the power to induce cell regeneration? Dr Catherine Berry - The Scotsman

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The new report by Expert Market Research titled, Global Stem Cell Banking Market Report and Forecast 2021-2026, gives an in-depth analysis of the globalstem cell banking market, assessing the market based on its segments like Service type, product type, utilisation, bank type, application, and major regions like Asia Pacific, Europe, North America, Middle East and Africa and Latin America. The report tracks the latest trends in the industry and studies their impact on the overall market. It also assesses the market dynamics, covering the key demand and price indicators, along with analysing the market based on the SWOT and Porters Five Forces models.

Request a free sample copy in PDF or view the report summary@https://bityl.co/CPix

The key highlights of the report include:

Market Overview (2021-2026)

The global stem cell bank market is primarily driven by the advancements in the field of medicine and the rising prevalence of genetic and degenerativediseases. Further, the increasing research and development of more effective technologies for better preservation, processing, and storage of stem cells are aiding the growth. Additionally, rising prevalence of chronic diseases globally is increasing the for advances inmedicaltechnologies, thus pushing the growth further. Moreover, factors such as rising health awareness, developinghealthcare infrastructure, growing geriatric population, and the inflatingdisposableincomes are expected to propel the market in the forecast period.

Industry Definition and Major Segments

Stem cells are undifferentiated cells present in bone marrow,umbilical cordadipose tissue and blood. They have the ability to of differentiate and regenerate. The process of storing and preserving these cells for various application such as gene therapy, regenerative medicine and tissue engineering is known as stem cell banking.

Explore the full report with the table of contents@https://bityl.co/CPiy

By service type, the market is divided into:

Based on product type, the industry can be segmented into:

The market is bifurcated based on utilization into:

By bank type, the industry can be broadly categorized into:

Based on application, the industry can be segmented into:

On the basis of regional markets, the industry is divided into:

1 North America1.1 United States of America1.2 Canada2 Europe2.1 Germany2.2 United Kingdom2.3 France2.4 Italy2.5 Others3 Asia Pacific3.1 China3.2 Japan3.3 India3.4 ASEAN3.5 Others4 Latin America4.1 Brazil4.2 Argentina4.3 Mexico4.4 Others5 Middle East & Africa5.1 Saudi Arabia5.2 United Arab Emirates5.3 Nigeria5.4 South Africa5.5 Others

Market Trends

Regionally, North America is projected to dominate the global stem cell bank market and expand at a significant rate. This can be attributed to increasing research and development for stem cell application in various medical fields. Further, growing investments of pharmaceutical players and development infrastructure are other factors that are expected to stem cell bank market in the region. Meanwhile, Asia Pacific market is also expected to witness fast growth owing to the rapid development in healthcare facilities and increasing awareness of stem cell banking in countries such as China, India, and Indonesia.

Key Market Players

The major players in the market are Cryo-Cell International, Inc., Smart Cells International Ltd., CSG-BIO Company, Inc., CBR Systems Inc., ViaCord, LLC, LifeCell International Pvt. Ltd., and a few others. The report covers the market shares, capacities, plant turnarounds, expansions, investments and mergers and acquisitions, among other latest developments of these market players.

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Global Stem Cell Banking Market To Be Driven At A CAGR Of 13.5% In The Forecast Period Of 2021-2026 This Is Ardee - This Is Ardee

Bone Marrow Stem Cells Comments Off on Global Stem Cell Banking Market To Be Driven At A CAGR Of 13.5% In The Forecast Period Of 2021-2026 This Is Ardee – This Is Ardee | July 25th, 2022

Country

United States of AmericaUS Virgin IslandsUnited States Minor Outlying IslandsCanadaMexico, United Mexican StatesBahamas, Commonwealth of theCuba, Republic ofDominican RepublicHaiti, Republic ofJamaicaAfghanistanAlbania, People's Socialist Republic ofAlgeria, People's Democratic Republic ofAmerican SamoaAndorra, Principality ofAngola, Republic ofAnguillaAntarctica (the territory South of 60 deg S)Antigua and BarbudaArgentina, Argentine RepublicArmeniaArubaAustralia, Commonwealth ofAustria, Republic ofAzerbaijan, Republic ofBahrain, Kingdom ofBangladesh, People's Republic ofBarbadosBelarusBelgium, Kingdom ofBelizeBenin, People's Republic ofBermudaBhutan, Kingdom ofBolivia, Republic ofBosnia and HerzegovinaBotswana, Republic ofBouvet Island (Bouvetoya)Brazil, Federative Republic ofBritish Indian Ocean Territory (Chagos Archipelago)British Virgin IslandsBrunei DarussalamBulgaria, People's Republic ofBurkina FasoBurundi, Republic ofCambodia, Kingdom ofCameroon, United Republic ofCape Verde, Republic ofCayman IslandsCentral African RepublicChad, Republic ofChile, Republic ofChina, People's Republic ofChristmas IslandCocos (Keeling) IslandsColombia, Republic ofComoros, Union of theCongo, Democratic Republic ofCongo, People's Republic ofCook IslandsCosta Rica, Republic ofCote D'Ivoire, Ivory Coast, Republic of theCyprus, Republic ofCzech RepublicDenmark, Kingdom ofDjibouti, Republic ofDominica, Commonwealth ofEcuador, Republic ofEgypt, Arab Republic ofEl Salvador, Republic ofEquatorial Guinea, Republic ofEritreaEstoniaEthiopiaFaeroe IslandsFalkland Islands (Malvinas)Fiji, Republic of the Fiji IslandsFinland, Republic ofFrance, French RepublicFrench GuianaFrench PolynesiaFrench Southern TerritoriesGabon, Gabonese RepublicGambia, Republic of theGeorgiaGermanyGhana, Republic ofGibraltarGreece, Hellenic RepublicGreenlandGrenadaGuadaloupeGuamGuatemala, Republic ofGuinea, RevolutionaryPeople's Rep'c ofGuinea-Bissau, Republic ofGuyana, Republic ofHeard and McDonald IslandsHoly See (Vatican City State)Honduras, Republic ofHong Kong, Special Administrative Region of ChinaHrvatska (Croatia)Hungary, Hungarian People's RepublicIceland, Republic ofIndia, Republic ofIndonesia, Republic ofIran, Islamic Republic ofIraq, Republic ofIrelandIsrael, State ofItaly, Italian RepublicJapanJordan, Hashemite Kingdom ofKazakhstan, Republic ofKenya, Republic ofKiribati, Republic ofKorea, Democratic People's Republic ofKorea, Republic ofKuwait, State ofKyrgyz RepublicLao People's Democratic RepublicLatviaLebanon, Lebanese RepublicLesotho, Kingdom ofLiberia, Republic ofLibyan Arab JamahiriyaLiechtenstein, Principality ofLithuaniaLuxembourg, Grand Duchy ofMacao, Special Administrative Region of ChinaMacedonia, the former Yugoslav Republic ofMadagascar, Republic ofMalawi, Republic ofMalaysiaMaldives, Republic ofMali, Republic ofMalta, Republic ofMarshall IslandsMartiniqueMauritania, Islamic Republic ofMauritiusMayotteMicronesia, Federated States ofMoldova, Republic ofMonaco, Principality ofMongolia, Mongolian People's RepublicMontserratMorocco, Kingdom ofMozambique, People's Republic ofMyanmarNamibiaNauru, Republic ofNepal, Kingdom ofNetherlands AntillesNetherlands, Kingdom of theNew CaledoniaNew ZealandNicaragua, Republic ofNiger, Republic of theNigeria, Federal Republic ofNiue, Republic ofNorfolk IslandNorthern Mariana IslandsNorway, Kingdom ofOman, Sultanate ofPakistan, Islamic Republic ofPalauPalestinian Territory, OccupiedPanama, Republic ofPapua New GuineaParaguay, Republic ofPeru, Republic ofPhilippines, Republic of thePitcairn IslandPoland, Polish People's RepublicPortugal, Portuguese RepublicPuerto RicoQatar, State ofReunionRomania, Socialist Republic ofRussian FederationRwanda, Rwandese RepublicSamoa, Independent State ofSan Marino, Republic ofSao Tome and Principe, Democratic Republic ofSaudi Arabia, Kingdom ofSenegal, Republic ofSerbia and MontenegroSeychelles, Republic ofSierra Leone, Republic ofSingapore, Republic ofSlovakia (Slovak Republic)SloveniaSolomon IslandsSomalia, Somali RepublicSouth Africa, Republic ofSouth Georgia and the South Sandwich IslandsSpain, Spanish StateSri Lanka, Democratic Socialist Republic ofSt. HelenaSt. Kitts and NevisSt. LuciaSt. Pierre and MiquelonSt. Vincent and the GrenadinesSudan, Democratic Republic of theSuriname, Republic ofSvalbard & Jan Mayen IslandsSwaziland, Kingdom ofSweden, Kingdom ofSwitzerland, Swiss ConfederationSyrian Arab RepublicTaiwan, Province of ChinaTajikistanTanzania, United Republic ofThailand, Kingdom ofTimor-Leste, Democratic Republic ofTogo, Togolese RepublicTokelau (Tokelau Islands)Tonga, Kingdom ofTrinidad and Tobago, Republic ofTunisia, Republic ofTurkey, Republic ofTurkmenistanTurks and Caicos IslandsTuvaluUganda, Republic ofUkraineUnited Arab EmiratesUnited Kingdom of Great Britain & N. IrelandUruguay, Eastern Republic ofUzbekistanVanuatuVenezuela, Bolivarian Republic ofViet Nam, Socialist Republic ofWallis and Futuna IslandsWestern SaharaYemenZambia, Republic ofZimbabwe

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He's the match: Arconic employee gets call 20 years after signing up to be bone marrow donor - Maryville Daily Times

Bone Marrow Stem Cells Comments Off on He’s the match: Arconic employee gets call 20 years after signing up to be bone marrow donor – Maryville Daily Times | July 25th, 2022

SINGAPORE - A Singaporean doctorwho is one of the top cell therapy experts in the worldhas been appointed to a World Health Organisation (WHO) expert panel.

Dr Mickey Koh is so sought-after in his field that for the past 15 years, he has been holding two jobs in two different countries.

The 56-year-old shuttles between England and Singapore, spending six weeks at a time in London, where he oversees the haematology department and looks after bone marrow transplant patients at St George's University Hospital, before returning to Singapore for a week and a half to head the cell therapy programme at the Health Sciences Authority.

Cell therapy is a growing field of medicine that uses living cells as treatment for a variety of diseases and conditions. This is an increasingly important therapeutic area and both his employers have agreed to his unusual schedule.

Over in London, Dr Koh is head of the Haematology Department at St George's Hospital and Medical School. In Singapore, he is the programme and medical director of the cell and gene therapy facility at the Health Sciences Authority.

In May, Dr Koh was selected to be on the WHO Expert Advisory Panel on Biological Standardisation.

Individuals on the panel have to be invited by WHO to apply, and are well recognised in their respective scientific fields. Eminent names on the panel include the current president of the Paul-Ehrlich-Institut in Germany, which is the country's federal agency, medical regulatory body and research institution for vaccines and biomedicine.

The WHO panel, which is made up of about 25 members, provides detailed recommendations and guidelines for the manufacturing, licensing and standardisation of biological products, which include blood, monoclonal antibodies, vaccines and, increasingly, cell-based therapeutics.

The recommendations and advice are passed on to the executive board of the World Health Assembly, which is the decision-making body of WHO.

Dr Koh's role had to be endorsed by the British government and was a direct appointment by the director-general of WHO.

His appointment as a panel expert will last for a term of four years.

Speaking to The Straits Times, Dr Koh shared his thoughts about the importance of regulation: "We are well aware that there is a very lucrative worldwide market peddling unproven stem cell treatments, where side effects are often unknown, and such unregulated practice can result in serious harm.

"This is already happening. People are claiming that you can use stem cells to treat things like ageing, and even very serious conditions like strokes, without any evidence."

With many medications now taking the form of biologics - a drug product derived from biological sources such as cells - the next wave of treatment would be the utilisation of these cells for the treatment of a wide range of diseases, Dr Koh said.

Excerpt from:
S'porean doctor, a sought-after top expert in cell therapy, appointed to WHO expert panel - The Straits Times

Bone Marrow Stem Cells Comments Off on S’porean doctor, a sought-after top expert in cell therapy, appointed to WHO expert panel – The Straits Times | July 25th, 2022

Tecartus (Brexucabtagene Autoleucel) First and Only CAR T in Europe to Receive Positive CHMP Opinion to Treat Adults 26+ with r/r ALL

If Approved, it will Address a Significant Unmet Need for a Patient Population with Limited Treatment Options

SANTA MONICA, Calif.--(BUSINESS WIRE)--Kite, a Gilead Company (Nasdaq: GILD), today announces that the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion for Tecartus (brexucabtagene autoleucel) for the treatment of adult patients 26 years of age and above with relapsed or refractory (r/r) B-cell precursor acute lymphoblastic leukemia (ALL). If approved, Tecartus will be the first and only Chimeric Antigen Receptor (CAR) T-cell therapy for this population of patients who have limited treatment options. Half of adults with ALL will relapse, and median overall survival (OS) for this group is only approximately eight months with current standard-of-care treatments.

Kites goal is clear: to bring the hope of survival to more patients with cancer around the world through cell therapy, said Christi Shaw, CEO, Kite. Todays CHMP positive opinion in adult ALL brings us a step closer to delivering on the promise that cell therapies have to transform the way cancer is treated.

Following this positive opinion, the European Commission will now review the CHMP opinion; the final decision on the Marketing Authorization is expected in the coming months.

Adults with relapsed or refractory ALL often undergo multiple treatments including chemotherapy, targeted therapy and stem cell transplant, creating a significant burden on a patients quality of life, said Max S. Topp, MD, professor and head of Hematology, University Hospital of Wuerzburg, Germany. If approved, patients in Europe will have a meaningful advancement in treatment. Tecartus has demonstrated durable responses, suggesting the potential for long-term remission and a new approach to care.

Results from the ZUMA-3 international multicenter, single-arm, open-label, registrational Phase 1/2 study of adult patients (18 years old) with relapsed or refractory ALL, demonstrated that 71% of the evaluable patients (n=55) achieved complete remission (CR) or CR with incomplete hematological recovery (CRi) with a median follow-up of 26.8 months. In an extended data set of all patients dosed with the pivotal dose (n=78) the median overall survival for all patients was more than two years (25.4 months) and almost four years (47 months) for responders (patients who achieved CR or CRi). Among efficacy-evaluable patients, median duration of remission (DOR) was 18.6 months. Among the patients treated with Tecartus at the target dose (n=100), Grade 3 or higher cytokine release syndrome (CRS) and neurologic events occurred in 25% and 32% of patients, respectively, and were generally well-managed.

About ZUMA-3

ZUMA-3 is an ongoing international multicenter (US, Canada, EU), single arm, open label, registrational Phase 1/2 study of Tecartus in adult patients (18 years old) with ALL whose disease is refractory to or has relapsed following standard systemic therapy or hematopoietic stem cell transplantation. The primary endpoint is the rate of overall complete remission or complete remission with incomplete hematological recovery by central assessment. Duration of remission and relapse-free survival, overall survival, minimal residual disease (MRD) negativity rate, and allo-SCT rate were assessed as secondary endpoints.

About Acute Lymphoblastic Leukemia

ALL is an aggressive type of blood cancer that develops when abnormal white blood cells accumulate in the bone marrow until there isnt any room left for blood cells to form. In some cases, these abnormal cells invade healthy organs and can also involve the lymph nodes, spleen, liver, central nervous system and other organs. The most common form is B cell precursor ALL. Globally, approximately 64,000 people are diagnosed with ALL each year, including around 3,300 people in Europe.

About Tecartus

Please see full FDA Prescribing Information, including BOXED WARNING and Medication Guide.

Tecartus is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:

This indication is approved under accelerated approval based on overall response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

U.S. IMPORTANT SAFETY INFORMATION

BOXED WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES

Cytokine Release Syndrome (CRS), including life-threatening reactions, occurred following treatment with Tecartus. In ZUMA-2, CRS occurred in 91% (75/82) of patients receiving Tecartus, including Grade 3 CRS in 18% of patients. Among the patients who died after receiving Tecartus, one had a fatal CRS event. The median time to onset of CRS was three days (range: 1 to 13 days) and the median duration of CRS was ten days (range: 1 to 50 days). Among patients with CRS, the key manifestations (>10%) were similar in MCL and ALL and included fever (93%), hypotension (62%), tachycardia (59%), chills (32%), hypoxia (31%), headache (21%), fatigue (20%), and nausea (13%). Serious events associated with CRS included hypotension, fever, hypoxia, tachycardia, and dyspnea.

Ensure that a minimum of two doses of tocilizumab are available for each patient prior to infusion of Tecartus. Following infusion, monitor patients for signs and symptoms of CRS daily for at least seven days for patients with MCL and at least 14 days for patients with ALL at the certified healthcare facility, and for four weeks thereafter. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated.

Neurologic Events, including those that were fatal or life-threatening, occurred following treatment with Tecartus. Neurologic events occurred in 81% (66/82) of patients with MCL, including Grade 3 in 37% of patients. The median time to onset for neurologic events was six days (range: 1 to 32 days) with a median duration of 21 days (range: 2 to 454 days) in patients with MCL. Neurologic events occurred in 87% (68/78) of patients with ALL, including Grade 3 in 35% of patients. The median time to onset for neurologic events was seven days (range: 1 to 51 days) with a median duration of 15 days (range: 1 to 397 days) in patients with ALL. For patients with MCL, 54 (66%) patients experienced CRS before the onset of neurological events. Five (6%) patients did not experience CRS with neurologic events and eight patients (10%) developed neurological events after the resolution of CRS. Neurologic events resolved for 119 out of 134 (89%) patients treated with Tecartus. Nine patients (three patients with MCL and six patients with ALL) had ongoing neurologic events at the time of death. For patients with ALL, neurologic events occurred before, during, and after CRS in 4 (5%), 57 (73%), and 8 (10%) of patients; respectively. Three patients (4%) had neurologic events without CRS. The onset of neurologic events can be concurrent with CRS, following resolution of CRS or in the absence of CRS.

The most common neurologic events (>10%) were similar in MCL and ALL and included encephalopathy (57%), headache (37%), tremor (34%), confusional state (26%), aphasia (23%), delirium (17%), dizziness (15%), anxiety (14%), and agitation (12%). Serious events including encephalopathy, aphasia, confusional state, and seizures occurred after treatment with Tecartus.

Monitor patients daily for at least seven days for patients with MCL and at least 14 days for patients with ALL at the certified healthcare facility and for four weeks following infusion for signs and symptoms of neurologic toxicities and treat promptly.

REMS Program: Because of the risk of CRS and neurologic toxicities, Tecartus is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta and Tecartus REMS Program which requires that:

Hypersensitivity Reactions: Serious hypersensitivity reactions, including anaphylaxis, may occur due to dimethyl sulfoxide (DMSO) or residual gentamicin in Tecartus.

Severe Infections: Severe or life-threatening infections occurred in patients after Tecartus infusion. Infections (all grades) occurred in 56% (46/82) of patients with MCL and 44% (34/78) of patients with ALL. Grade 3 or higher infections, including bacterial, viral, and fungal infections, occurred in 30% of patients with ALL and MCL. Tecartus should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after Tecartus infusion and treat appropriately. Administer prophylactic antimicrobials according to local guidelines.

Febrile neutropenia was observed in 6% of patients with MCL and 35% of patients with ALL after Tecartus infusion and may be concurrent with CRS. The febrile neutropenia in 27 (35%) of patients with ALL includes events of febrile neutropenia (11 (14%)) plus the concurrent events of fever and neutropenia (16 (21%)). In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids, and other supportive care as medically indicated.

In immunosuppressed patients, life-threatening and fatal opportunistic infections have been reported. The possibility of rare infectious etiologies (e.g., fungal and viral infections such as HHV-6 and progressive multifocal leukoencephalopathy) should be considered in patients with neurologic events and appropriate diagnostic evaluations should be performed.

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

Prolonged Cytopenias: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Tecartus infusion. In patients with MCL, Grade 3 or higher cytopenias not resolved by Day 30 following Tecartus infusion occurred in 55% (45/82) of patients and included thrombocytopenia (38%), neutropenia (37%), and anemia (17%). In patients with ALL who were responders to Tecartus treatment, Grade 3 or higher cytopenias not resolved by Day 30 following Tecartus infusion occurred in 20% (7/35) of the patients and included neutropenia (12%) and thrombocytopenia (12%); Grade 3 or higher cytopenias not resolved by Day 60 following Tecartus infusion occurred in 11% (4/35) of the patients and included neutropenia (9%) and thrombocytopenia (6%). Monitor blood counts after Tecartus infusion.

Hypogammaglobulinemia: B cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with Tecartus. Hypogammaglobulinemia was reported in 16% (13/82) of patients with MCL and 9% (7/78) of patients with ALL. Monitor immunoglobulin levels after treatment with Tecartus and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement.

The safety of immunization with live viral vaccines during or following Tecartus treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least six weeks prior to the start of lymphodepleting chemotherapy, during Tecartus treatment, and until immune recovery following treatment with Tecartus.

Secondary Malignancies may develop. Monitor life-long for secondary malignancies. In the event that one occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

Effects on Ability to Drive and Use Machines: Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following Tecartus infusion. Advise patients to refrain from driving and engaging in hazardous activities, such as operating heavy or potentially dangerous machinery, during this period.

Adverse Reactions: The most common non-laboratory adverse reactions ( 20%) were fever, cytokine release syndrome, hypotension, encephalopathy, tachycardia, nausea, chills, headache, fatigue, febrile neutropenia, diarrhea, musculoskeletal pain, hypoxia, rash, edema, tremor, infection with pathogen unspecified, constipation, decreased appetite, and vomiting. The most common serious adverse reactions ( 2%) were cytokine release syndrome, febrile neutropenia, hypotension, encephalopathy, fever, infection with pathogen unspecified, hypoxia, tachycardia, bacterial infections, respiratory failure, seizure, diarrhea, dyspnea, fungal infections, viral infections, coagulopathy, delirium, fatigue, hemophagocytic lymphohistiocytosis, musculoskeletal pain, edema, and paraparesis.

About Kite

Kite, a Gilead Company, is a global biopharmaceutical company based in Santa Monica, California, with manufacturing operations in North America and Europe. Kites singular focus is cell therapy to treat and potentially cure cancer. As the cell therapy leader, Kite has more approved CAR T indications to help more patients than any other company. For more information on Kite, please visit http://www.kitepharma.com. Follow Kite on social media on Twitter (@KitePharma) and LinkedIn.

About Gilead Sciences

Gilead Sciences, Inc. is a biopharmaceutical company that has pursued and achieved breakthroughs in medicine for more than three decades, with the goal of creating a healthier world for all people. The company is committed to advancing innovative medicines to prevent and treat life-threatening diseases, including HIV, viral hepatitis and cancer. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, California.

Forward-Looking Statements

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the ability of Gilead and Kite to initiate, progress or complete clinical trials within currently anticipated timelines or at all, and the possibility of unfavorable results from ongoing and additional clinical trials, including those involving Tecartus; the risk that physicians may not see the benefits of prescribing Tecartus for the treatment of blood cancers; and any assumptions underlying any of the foregoing. These and other risks, uncertainties and other factors are described in detail in Gileads Quarterly Report on Form 10-Q for the quarter ended March 31, 2022 as filed with the U.S. Securities and Exchange Commission. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. The reader is cautioned that any such forward-looking statements are not guarantees of future performance and involve risks and uncertainties and is cautioned not to place undue reliance on these forward-looking statements. All forward-looking statements are based on information currently available to Gilead and Kite, and Gilead and Kite assume no obligation and disclaim any intent to update any such forward-looking statements.

U.S. Prescribing Information for Tecartus including BOXED WARNING, is available at http://www.kitepharma.com and http://www.gilead.com .

Kite, the Kite logo, Tecartus and GILEAD are trademarks of Gilead Sciences, Inc. or its related companies .

View source version on businesswire.com: https://www.businesswire.com/news/home/20220722005258/en/

Jacquie Ross, Investorsinvestor_relations@gilead.com

Anna Padula, Mediaapadula@kitepharma.com

Source: Gilead Sciences, Inc.

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Kite's CAR T-cell Therapy Tecartus Receives Positive CHMP Opinion in Relapsed or Refractory Acute Lymphoblastic Leukemia (r/r ALL) - Gilead Sciences

Bone Marrow Stem Cells Comments Off on Kite’s CAR T-cell Therapy Tecartus Receives Positive CHMP Opinion in Relapsed or Refractory Acute Lymphoblastic Leukemia (r/r ALL) – Gilead Sciences | July 25th, 2022

Market Overview

Thecell culture media marketis expected to cross USD 4.33 billion by 2027 at a CAGR of8.33%.

Market Dynamics

The markets growth is being fueled by a diverse range of cell culture media applications, increased research and development in the pharmaceutical industry, an increase in the prevalence of chronic diseases, and increased expansion and product launches by major players. Over the last few decades, advancements in cell culture technology have accelerated. It is widely regarded as one of the most dependable, robust, and mature technologies for biotherapeutic product development.

The high cost of cell culture media and the risk of contamination, on the other hand, are impeding the markets growth. However, the growing emphasis on regenerative and personalized medicine is likely to spur growth in the global cell culture media market.

Get Sample Report: https://www.marketresearchfuture.com/sample_request/4462

Competitive Dynamics

The notable players are the Merck KGaA (Germany), Bio-Rad Laboratories, Inc. (US), Thermo Fisher Scientific Inc. (US), Lonza (Switzerland), GE Healthcare (US), Becton, Dickinson and Company (US), HiMedia Laboratories (India), Corning Incorporated (US), PromoCell (Germany), Sera Scandia A/S (Denmark), The Sartorius Group (Germany), and Fujifilm Holdings Corporation (Japan).

Segmental Analysis

The global market for cell culture media has been segmented according to product type, application, and end user.

The market has been segmented by product type into classical media, stem cell media, serum-free media, and others.

Further subcategories of stem cell culture media include bone marrow, embryonic stem cells, mesenchymal stem cells, and neural stem cells.

The market is segmented into four application segments: drug discovery and development, cancer research, genetic engineering, and tissue engineering and biochemistry.

The market is segmented by end user into biochemistry and pharmaceutical companies, research laboratories, academic institutions, and pathology laboratories.

Regional Overview

According to region, the global cell culture media market is segmented into the Americas, Europe, Asia-Pacific, and the Middle East & Africa.

The Americas dominated the global cell culture media market. The large share is attributed to the presence of major manufacturers, rising disease prevalence resulting in increased demand for drugs and other medications, technological advancements in the preclinical and clinical segments, growing public awareness, and high disposable income.

Europe ranks second in terms of market size for cell culture media. Factors such as an increase in the biopharmaceutical sector in the European region, increased government initiatives to promote research to find a cure for the growing number of chronic diseases, an increase in the number of pharmaceutical manufacturers, improving economies, a high disposable income per individual, and increased healthcare spending are all contributing to the markets growth in this region. The European market is expected to be driven by expanding R&D activities and a developing biopharmaceutical sector.

Asia-Pacific held the third-largest market share, owing to the presence of numerous research organizations, low manufacturing costs, low labor costs, developing healthcare infrastructure, and increased investment by American and European market giants in Asian countries such as China and India.

The Middle East and Africa, with limited economic development and extremely low income, held the smallest market share in 2019 but is expected to grow due to growing public awareness and demand for improved healthcare facilities in countries, as well as rising disposable income.

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Cell Culture Media Market: Competitive Approach, Breakdown And Forecast by 2027 - Digital Journal

Bone Marrow Stem Cells Comments Off on Cell Culture Media Market: Competitive Approach, Breakdown And Forecast by 2027 – Digital Journal | July 25th, 2022

New Jersey, United States TheStem Cell TherapyMarket research guides new entrants to obtain precise market data and communicates with customers to know their requirements and preferences. It spots outright business opportunities and helps to bring new products into the market. It identifies opportunities in the marketplace. It aims at doing modifications in the business to make business procedures smooth and make business forward. It helps business players to make sound decision making. Stem Cell Therapy market report helps to reduce business risks and provides ways to deal with upcoming challenges. Market information provided here helps new entrants to take informed decisions making. It emphasizes on major regions of the globe such as Europe, North America, Asia Pacific, Middle East, Africa, and Latin America along with their market size.

Such unique Stem Cell Therapy Market research report offers some extensive strategic plans that help the players to deal with the current market situation and make your position. It helps in strengthening your business position. It offers better understanding of the market and keep perspective to aid one remain ahead in this competitive market. Organizations can gauze and compare their presentation with others in the market on the basis of this prompt market report. This market report offers a clarified picture of the varying market tactics and thereby helps the business organizations gain bigger profits. You get a clear idea about the product launches, trade regulations and expansion of the market place through this market report.

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Key Players Mentioned in the Stem Cell Therapy Market Research Report:

Osiris Therapeutics Medipost Co. Ltd., Anterogen Co. Ltd., Pharmicell Co. Ltd., HolostemTerapieAvanzateSrl, JCR Pharmaceuticals Co. Ltd., Nuvasive RTI Surgical Allosource

Stem Cell TherapyMarket report consists of important data about the entire market environment of products or services offered by different industry players. It enables industries to know the market scenario of a particular product or service including demand, supply, market structure, pricing structure, and trend analysis. It is of great assistance in the product market development. It further depicts essential data regarding customers, products, competition, and market growth factors. Stem Cell Therapy market research benefits greatly to make the proper decision. Future trends are also revealed for particular products or services to help business players in making the right investment and launching products into the market.

Stem Cell TherapyMarket Segmentation:

Stem Cell Therapy Market, By Cell Source

Adipose Tissue-Derived Mesenchymal Stem Cells Bone Marrow-Derived Mesenchymal Stem Cells Cord Blood/Embryonic Stem Cells Other Cell Sources

Stem Cell Therapy Market, By Therapeutic Application

Musculoskeletal Disorders Wounds and Injuries Cardiovascular Diseases Surgeries Gastrointestinal Diseases Other Applications

Stem Cell Therapy Market, By Type

Allogeneic Stem Cell Therapy Autologous Stem Cell Therapy

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For Prepare TOC Our Analyst deep Researched the Following Things:

Report Overview:It includes major players of the Stem Cell Therapy market covered in the research study, research scope, market segments by type, market segments by application, years considered for the research study, and objectives of the report.

Global Growth Trends:This section focuses on industry trends where market drivers and top market trends are shed light upon. It also provides growth rates of key producers operating in the Stem Cell Therapy market. Furthermore, it offers production and capacity analysis where marketing pricing trends, capacity, production, and production value of the Stem Cell Therapy market are discussed.

Market Share by Manufacturers:Here, the report provides details about revenue by manufacturers, production and capacity by manufacturers, price by manufacturers, expansion plans, mergers and acquisitions, and products, market entry dates, distribution, and market areas of key manufacturers.

Market Size by Type:This section concentrates on product type segments where production value market share, price, and production market share by product type are discussed.

Market Size by Application:Besides an overview of the Stem Cell Therapy market by application, it gives a study on the consumption in the Stem Cell Therapy market by application.

Production by Region:Here, the production value growth rate, production growth rate, import and export, and key players of each regional market are provided.

Consumption by Region:This section provides information on the consumption in each regional market studied in the report. The consumption is discussed on the basis of country, application, and product type.

Company Profiles:Almost all leading players of the Stem Cell Therapy market are profiled in this section. The analysts have provided information about their recent developments in the Stem Cell Therapy market, products, revenue, production, business, and company.

Market Forecast by Production:The production and production value forecasts included in this section are for the Stem Cell Therapy market as well as for key regional markets.

Market Forecast by Consumption:The consumption and consumption value forecasts included in this section are for the Stem Cell Therapy market as well as for key regional markets.

Value Chain and Sales Analysis:It deeply analyzes customers, distributors, sales channels, and value chain of the Stem Cell Therapy market.

Key Findings:This section gives a quick look at the important findings of the research study.

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Stem Cell Therapy Market Size, Scope, Growth Opportunities, Trends by Manufacturers And Forecast to 2029 This Is Ardee - This Is Ardee

Bone Marrow Stem Cells Comments Off on Stem Cell Therapy Market Size, Scope, Growth Opportunities, Trends by Manufacturers And Forecast to 2029 This Is Ardee – This Is Ardee | July 25th, 2022

Josh, Harper and Meagan in June 2022

Two years ago, Meagan stood in a hospital room at Seattle Childrens cradling her 1-year-old daughter, Harper, against her chest. Her fianc, Josh, huddled close to them and kissed the thinning hair on top of their babys head.

A feeding tube was routed through Harpers nose and her eyes were brimming with tears. Exhausted, she snuggled into her moms arms as a photographer took their picture.

Meagan and Josh feared those would be the last photos taken of their baby girl.

Six months before, Harper became seriously ill. After multiple visits to their pediatrician in Yakima, Meagan took her to an emergency room where blood tests revealed Harper had leukemia.

It was shocking, Meagan says. Thirty minutes later we were on an emergency flight to Seattle Childrens.

The family didnt return home for nearly two years.

The type of leukemia Harper had acute lymphoblastic leukemia (ALL) is typically harder to treat and has lower survival rates when it occurs in infants who are less than a year old.

Harpers case was exceptionally challenging. She didnt respond to standard chemotherapy, even after providers added a medication designed to sensitize her leukemia to the treatment.

Her care team, which included Seattle Childrens High-Risk Leukemia Program, believed a stem cell transplant would give Harper the best chance of surviving, but they had to eliminate the majority of her leukemia cells first.

Drs. Kasey Leger and Brittany Lee, Harpers primary oncologists, started her on a novel immunotherapy medication, called blinatumomab, which effectively destroyed many of her ALL cells.

Unfortunately, two weeks later, the team discovered some of Harpers ALL cells had morphed into a different blood cancer acute myeloid leukemia (AML). This rare occurrence, called lineage switch, occurs in less than 5% of infant ALL cases.

It was a roller coaster, Josh says. She didnt do anything they expected her to do. It felt like every day we had to come up with a new plan.

Drs. Leger and Lee gave Harper a different kind of chemotherapy that destroyed the new AML cells. Still, some of her ALL cells remained, so the team gave Harper blinatumomab again which finally suppressed her cancer enough for her to have a stem cell transplant just before her first birthday.

Harper and her mom, Meagan, celebrating Harpers first birthday shortly after her stem cell transplant

The team had done everything they could to get Harper healthy enough for a stem cell transplant, hopeful it would be the treatment that finally cured her. Tragically, Harpers leukemia was back less than a month later.

When leukemia comes back so soon after transplant, patients have very few treatment options, if any, says Dr. Corinne Summers, Harpers stem cell transplant specialist. Many patients will not survive long term.

Harpers parents were terrified they were going to lose her.

Her bone marrow was packed with leukemia, Josh remembers. You could tell the life was slipping out of her and she just looked like it was going to be the end.

After Harpers stem cell transplant failed, the family met with end-of-life specialists and scheduled a special photo session to create memories that they would carry forward

They struggled to decide if they should continue treatment.

How do you know when enough is enough? Meagan says. When do you say, We cant do this to her anymore? Harper couldnt tell us how she was feeling, so it was all our decision.

Meagan and Josh worked closely with the care team to decide what to do next.

Those conversations were emotional for all of us, says Dr. Lee. Thankfully, we had a close, trusting relationship with their family and were able to give recommendations that reflected what they wanted for their daughter and what they felt was most important.

After much consideration, Meagan and Josh decided Harper was strong enough to continue treatment.

Drs. Leger and Lee filed a compassionate use request with the Food and Drug Administration to give Harper an investigational chemotherapy drug called venetoclax. Unfortunately, the treatment didnt work.

Collaborating with the family, the team decided to try giving Harper blinatumomab one more time. There was no evidence suggesting the medication would work so soon after a bone marrow transplant and with such a high burden of leukemia, but within a week it eliminated 98% of Harpers cancer cells.

Family is a critical piece of the team, Dr. Leger says. And Harper is fortunate to have amazing parents who were at her bedside 24/7 and had a beautiful way of advocating for her. They challenged us to leave no stone unturned and partnered with us throughout her treatment to keep figuring out a way forward.

With Harpers leukemia under control, the team searched for a way to wipe out any remaining cancer cells and keep her disease from coming back. Doctors in Childrens Cancer and Blood Disorders Center lead national research groups such as the Childrens Oncology Group, so they have access to trials around the world. However, Harpers care team found the best treatment for her was at Seattle Childrens Hospital, in partnership with Seattle Childrens Therapeutics.

Harpers T-cells were removed through a process called apheresis before they were reprogrammed to target her cancer cells and infused back into her blood

Harper was enrolled in one of Childrens T-cell immunotherapy clinical trials. The treatment involves re-programming a patients T cells (a type of white blood cell) to target and destroy their cancer cells.

After her T-cell therapy, Harper was finally in remission.

Meagan cried with relief when she found out. Harper would not be here right now if it wasnt for everybody at Seattle Childrens, she says. From day one, theyve been comforting and compassionate. They bend over backwards to keep families involved and helped us fight for our child.

To keep her in remission, Harper was given six antigen-presenting cell boosters, which kept her reprogrammed T cells circulating through her blood longer. She received the last booster earlier this year and is still in remission today.

Harper had a very unique disease in that her leukemia manifested as both ALL and AML, says Dr. Leger. Thankfully, we have team members with deep expertise in each of those diseases. Having internationally recognized chemotherapy, transplant and immunotherapy specialists on our team allowed us to be creative with her care when she needed to go beyond the standard pathways.

Today, Harper is a joyful, boisterous 3-year-old who loves experimenting with musical toys and splashing around in her bath or kiddie pool. One of her favorite things to do is grab Meagan by the hair and squish their faces together.

Because of the treatments Harper received at such a young age and the extended time she spent in the hospital, Harper is behind on some developmental milestones like speaking and walking. Still, Meagan and Josh say shes catching up.

Shes starting to bloom and take off and its so nice to see, Meagan says. At the same time, we cant get too comfortable. We know how relentless her disease is and that it could come back one day.

Harper plays in a pool, one of her favorite activities, in June 2022

Harpers family encourages community members to support cancer research at Childrens so that new treatments can be developed for Harper and other kids like her.

Without donors, Harper probably wouldnt be alive right now, Josh says. The treatments she had were developed in just the last few years. If people dont step up and donate, those programs arent there. Those drugs arent invented. Cancer treatment has come a really long way and thats because of donors stepping up to make that happen.

Learn more about Seattle Childrens High-Risk Leukemia Program and Cancer and Blood Disorders Center.

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Bone Marrow Stem Cells Comments Off on No Stone Unturned: Seattle Children’s High-Risk Leukemia Experts Specialize in the Toughest Cases – On the Pulse – On the Pulse | July 25th, 2022