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

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

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

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

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

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

About Tevogen Bio

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

About HMP Partners

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

About Dr. Neal Flomenberg

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

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

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

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

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

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

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

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

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

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

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

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

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

Bone marrow is the tissue inside of bones.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Background

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The authors report no conflicts of interest in this work.

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The single-use device market is primed for growth. Single-use systems (SUS) are now used for about 85 percent of precommercial scale (preclinical and clinical) biopharmaceutical manufacturing and increasingly for commercial products manufacturing. This shift from fixed stainless steel appears to be revolutionizing the therapeutics market.

While large-scale, fixed stainless-steel equipment-based bioprocessing facilities continue producing biopharmaceuticals, the market for SUS, composed primarily of plastic components that are sealed and sterilized using gamma irradiation, continues its rapid ascent. Medical device makers are seeing growth in single-use instruments and disposable medical devices, including process containers, tubing, connectors, baskets, and valves. According to Grand View Research, in 2019, the global SUS market was valued at $12.6 billion, with a 12.8 percent compound annual growth rate forecast through 2027, when it will top $33 billion.

Lower energy and direct-labor costs plus faster changeover times are important reasons why. Like any major change, the SUS shift brings with it challenges as pharmaceutical manufacturers and medical device makers turn to their suppliers to provide assurance that their products deploy operational best practices and are certifiably safe.

To address key challenges in the SUS market and meet the product development needs of Tier 1 pharmaceutical and medical device companies, collaboration is seen between Tier 2 system suppliers and Tier 3 components suppliers.

One such effort comes in the form of the BioPhorum Operations Group, a global collaboration comprising more than 90 Tier 1, 2 and 3 biopharmaceutical companies and suppliers; its purpose is to develop and share best practices for pharmaceutical and medical device manufacturing. For example, BioPhorum has succeeded in establishing effective testing methods for extractables and leachables to help the industry approve SUS for safe and effective use.

To select processing materials that avoid risk, its important to understand the chemical nature of extractables, which are compounds emitted from a packaging component, delivery system, or manufacturing surface during aggressive testing; and leachables, which are compounds that migrate into the drug over time from contact with the system componentry and manufacturing surfaces.

To assist suppliers with their evaluation of SUS extractables, the BioPhorum team developed testing protocols based on a set of solvents and immersion times. Adhering to such protocols helps ensure the successful use of SUS for biopharmaceutical manufacturing, though the final responsibility for confirming the safety and efficacy of the therapeutic remains that of the Tier 1 pharmaceutical companies and medical device makers, not their suppliers.

Complementing the BioPhorum extractables protocol is a best practice guide for evaluating SUS leachables. BioPhorum protocol applies to SUS components that contact the pharmaceutical product or process fluids, including but not limited to the medical device/drug delivery market:

Note: The standardized extractables testing protocol does not cover final container closure systems.

Achieving medical-grade system components requires treating the part as a medical product when it comes to cleanroom and manufacturing practices. For tubing, for example, its no longer acceptable to manufacture medical-device-grade tubing on the production floor and then attempt to sterilize it. Tubing production for any medical device must take place in ISO certified cleanrooms that adhere to FDA's Current Good Manufacturing Practices governing particulates, air pressure, and personnel practices to ensure that products meet tolerance and cleanliness requirements. This may require bioburden and endotoxin testing.

These procedures help ensure production of safe, validated products in critical areas such as the transfer of monoclonal antibodies, laboratory-produced base media for therapeutics engineered to represent the bodys immunes system and used in the development of cancer-treating therapeutics. The tubing must be bacteria-free and remain strong as it transfers the monoclonal antibodies to the bioreactor and chromatography equipment, where wanted therapeutics are filtered out.

Other single-use tubing applications include peristaltic pumps with rotating wheels that push the fluid through tubes. To withstand the rigors of the pumping process and ensure that the tubing walls remain intact, high-strength tubing is required.

Advancements in therapeutics will continue driving the development and growth of SUS and their components. One such advancementchimeric antigen receptor (CAR T) cell therapy under development by Kite, a Gilead Companytaps into the potential of personalized medicine for cancer treatments, using the patients immune system to target and attack tumors.

T-cells, a white blood cell developed from stem cells in the bone marrow, help the body to fight cancer and infections. Currently, three FDA-approved CAR T cell therapies, developed by Gilead and Novartis, are available. There is also exponential growth of other biotechnology and pharmaceutical companies actively advancing cellular immunotherapies through clinical trials.

Investigational for now, the safety and efficacy of T-cell therapy is an active area of research, and it could prove to be a game-changer. A cancer patients blood is collected and purified to select the T-cells, which are activated and expanded within the lab and transfected to express a chimeric antigen receptor, or synthetic T-cell receptor, targeting a specific tumor antigen. The T-cells grow and expand for two weeks and are then infused back into the patient where the engineered cells attack the tumors. This chain of events requires a precise timeline with all components of the process being sterile and having passed stringent testing for quality and reliability.

Unlocking the immune system to effectively fight cancer is truly exciting and serves as a great illustration of the potential medical device use of SUS in biopharmaceutical processing.

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Onward and Upward for Single-Use Systems in Bioprocessing - Medical Device and Diagnostics Industry

Bone Marrow Stem Cells Comments Off on Onward and Upward for Single-Use Systems in Bioprocessing – Medical Device and Diagnostics Industry | January 27th, 2021

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KOCHI:How would a two-year-old child react when she meets her lifes saviour in real life? It is quite hard to imagine. Or from the other side, the reaction of the person who sees, after two years, the face of the infant he rescued from certain death.

At times, emotions just abound, beyond what words can express! Tears of joy rolled down Amir's face, when he first met two-year-old Vihaa Khanekar, to whom he had donated his blood stem cells in 2019, on Saturday.

The four-hour-long video call that Amir made to Vihaa and her family members late on Saturday made him make up his mind to fly to Pune soon to meet Vihaa. A Pune resident, Vihaa was diagnosed with Juvenile Myelomonocytic Leukemia (JML), when she was barely four-and-a-half months' old. Bone marrow transplant was the only hope and her parents were devastated.

"When we first heard the news it was as if we were hit by a hailstorm. It was known that our daughters condition was a rare one and that it was difficult for her to get a transplant. Her father swooned and even her mother almost had a blackout. The whole family came together to support them," said Dnyaneshwar Khanekar, Vihaas grandfather.

Vihaa received the cells in September 2019. "She was diagnosed with the illness in March. It is Amir who saved her life. In 2018, Amir had registered with the DATRI-Blood Stem Donors Registry in Aluva. His blood stem cells were a match and Amir was happy to donate them,"said Aby Sam John, DATRI Kerala- Maharastra Regional head.

26-year-old Amir Suhail Hussain, a resident of Nedumbassery, is not only happy about saving a life, but he also urged like-minded people to come forward. "When I came to know about Vihaa, I had no hesitation. However, my kin, particularly my parents, were anxious, more so because they were ignorant about the whole process. After assurances from doctors, they came to terms with my decision," said Amir.

According to Vihaas parents, her condition is better, with no complications. The transplant took place at a private hospital in Pune. "Though Amir is not known to us, his generosity has overwhelmed us," said Sandeep Khanekar, Vihaa's father.

The Saviour and Survivor meet was held by DATRI as part of creating awareness among many about donating stem cells and saving lives. The meet was organised virtually. DATRI - Indias largest blood stem cell donor registry - has 4,61,627 donors registered. A total of 773 people have donated their blood stem cells.

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From Kochi, with love - Stem cell donor meets infant survivor after two years - The New Indian Express

Bone Marrow Stem Cells Comments Off on From Kochi, with love – Stem cell donor meets infant survivor after two years – The New Indian Express | January 25th, 2021

Life for Miro, a 5-year-old German shepherd, has been what his owner describes as an emotional roller coaster over the past two years. Several peaks and valleys have dotted his metaphorical landscape as he has gone from premiere fitness to dealing with injuries and disease. But a clinical trial at the UC Davis veterinary hospital may have put him back on a positive track.

Working as a patrol dog with his handler/owner Martin Gilbertson, a ranger with California State Parks, Miro spent three years performing duties that required him to be at the top of his game. In early 2019, he was just that, having won the top dog award for his department.

By that summer, however, things started declining for Miro. He was diagnosed with lumbosacral intervertebral disc disease that caused spinal cord compression. UC Davis veterinary neurosurgeons performed a surgical decompression, and Miro eventually recovered after a lengthy recuperation period.

Miro with his handler Martin Gilbertson

Life was great, said Gilbertson. By early December 2019, Miro was cleared to return to work. I thought all the troubles were behind us.

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It only took a few weeks, though, until the roller coaster cleared a peak and started to descend.

In late December 2019, Miro collapsed for no apparent reason and started shaking in a way Gilbertson had never seen. So, the pair returned to UC Davis where Miro was diagnosed with myasthenia gravis, a disease in which there is a malfunction in the transmission of signals between the nerves and muscles. This causes muscle weakness, and an inability to walk or run properly, as well as potentially devastating neuromuscular disorders.

Gilbertson was devastated.

To go from the pinnacle of our profession to potentially being a couch potato at best for the rest of his life was a real gut check, he said.

But hope appeared a few weeks later when Neurology/Neurosurgery Service faculty members Drs. Pete Dickinson and Bev Sturges informed Gilbertson of a myasthenia gravis clinical trial they were beginning with the help of the schools Center for Companion Animal Health (CCAH) and the Veterinary Institute for Regenerative Cures.

I thought, What do we have to lose? stated Gilbertson. Dr. Dickinson told me that Miro would be the first dog to ever receive this new treatment. We were excited and grateful to be able to participate.

A computer program shows Miro's stride pattern on the Tekscan Strideway pressure walkway.

Over the next few months, Miro received three stem cell treatments, as well as traditional medications to treat myasthenia gravis. Additionally, part of Miros recovery involved examining his gait, which utilized a new piece of equipment aimed at better analyzing a dogs stride pattern. Thanks to CCAH funding, the school recently acquired a Tekscan Strideway pressure walkway that allows clinicians and researchers to better gauge a patients step pattern and make decisions about their optimal care and recovery. To fully understand a patients gait abnormalities associated with injuries or neuromuscular diseases, veterinarians and researchers rely on objective, quantitative ways to assess locomotor function. The Strideway system complements the force plates in the schools J.D. Wheat Veterinary Orthopedic Research Laboratory, which captures extensive information, but only for one gait step. The new pressure walkway expands the capabilities to quantify pressure, vertical force, and stride parameters (timing and spacing) on all limbs for several strides during walking, trotting or landing. Miros progress was able to be tracked with pinpoint accuracy throughout his recovery.

Before the trial, Miro could only walk about 10 steps before falling down. After the trial, he seemed fully recovered, and blood tests revealed no trace of antibodies to the disease. While the disease may not be completely gone from his system, the clinical trial seems to have repressed the disease to a point where it no longer inhibits Miro from his normal activities. Retired from his job, Miro now enjoys life as a family pet.

It is true that Miro is now in remission, but until more analysis of data is completed, it is still too early to determine if the stem cells were the driving force behind his recovery, since they were administered at the same time as standard-of-care medications. Miros results are being closely examined, along with the results of two other dogs that have completed the trial, to see if this stem cells treatment truly can be considered a cure for myasthenia gravis. Regardless of the final outcome of the study, Miros recovery, in one way or another, came from a novel combination of treatments pioneered at UC Davis.

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Novel Treatment Leads to Dog's Recovery - The Bark

Spinal Cord Stem Cells Comments Off on Novel Treatment Leads to Dog’s Recovery – The Bark | January 25th, 2021

Researchers at the National Institutes of Health have discovered a new genetic disorder characterized by developmental delays and malformations of the brain, heart and facial features. Named linkage-specific-deubiquitylation-deficiency-induced embryonic defects syndrome (LINKED), it is caused by a mutated version of the OTUD5 gene, which interferes with key molecular actions in embryo development.

The findings indicate that the newly identified pathway may be essential for human growth and may also underlie other disorders that are present at birth. The information will help scientists better understand such diseasesboth common and rareand enhance patient care. The results were reported Jan. 20, 2021 at Science Advances.

The project began when David B. Beck, M.D., Ph.D., a clinical fellow in the laboratory of Dan Kastner M.D., Ph.D., at the National Human Genome Research Institute (NHGRI) and co-first author, was asked to consult on a male baby who had been born with severe birth defects that included abnormalities of the brain, craniofacial skeleton, heart and urinary tract.

Our discovery of the dysregulated neurodevelopmental pathway that underlies LINKED syndrome was only possible through the teamwork of geneticists, developmental biologists and biochemists from NIH,. This collaboration provided the opportunity to pinpoint the likely genetic cause of disease, and then take it a step further to precisely define the sequence of cellular events that are disrupted to cause the disease.

Achim Werner, Ph.D., Investigator, National Institute of Dental and Craniofacial Research (NIDCR) and Lead Author

An in-depth examination of siblings and family members genomes, combined with hereditary bioinformatics analyses, revealed a mutation in the OTUD5 gene as the possible cause of the problem. Through outreach to other researchers working on similar problems, Beck found seven additional males ranging from 1 to 14 years of age who shared symptoms with the first patient and had varying mutations in the OTUD5 gene.

The gene comprises instructions for making the OTUD5 enzyme, which is involved in ubiquitylation, a process which molecularly alters a protein to change its purpose. Ubiquitylation plays a part in governing cell fate, where stem cells are taught to turn into specific cell types in the early stages of embryo development.

According to the genetic evidence, I was pretty sure OTUD5 mutations caused the disease, but I did not understand how this enzyme, when mutated, led to the symptoms seen in our patients, said Beck. For this reason we sought to work with Dr. Werners group, which specializes in using biochemistry to comprehend the functions of enzymes such as OTUD5.

To begin, the NIH team analyzed cells taken from patient samples, which were processed in the NIH Clinical Center. Usually, OTUD5 edits or eliminates molecular tags on particular proteins (substrates) to modulate their function. However, in cells from patients with OTUD5 mutations, this activity was diminished.

Using a method to reunite mature human cells into the stem cell-like state of embryo cells, the scientists discovered that OTUD5 mutations were linked to abnormalities in the development of neural crest cells, which give rise to tissues of the craniofacial skeleton, and of neural precursors, cells that eventually give rise to the brain and spinal cord.

In additional experiments, the team discovered that the OTUD5 enzyme acts on a few protein substrates called chromatin remodelers. This class of proteins alters the closely packed strands of DNA in a cells nucleus to make sure genes accessible for being turned on, or expressed.

With help from collaborators led by Pedro Rocha Ph.D., an investigator in the National Institute of Child Health and Human Development (NICHD), the group found that chromatin remodelers targeted by OTUD5 help enhance expression of genes that control the cell fate of neural precursors during embryo development.

Taken together, the investigators reasoned, OTUD5 normally keeps these chromatin remodelers from being tagged for destruction. However, while OTUD5 is mutated, its protective function is lost and the chromatin remodelers are destroyed, leading to abnormal development of neural precursors and neural crest cells. Ultimately, these changes can lead to some of the birth defects seen in LINKED patients.

This implies that the mechanism we discovered is a portion of a common developmental pathway that, when mutated at different points, will result in a spectrum of disease.

We were amazed to discover that OTUD5 elicits its effects via multiple, functionally related substrates, which shows a new principle of cellular signaling during early embryonic development, said Mohammed A. Basar, Ph.D., a postdoctoral fellow in Werners lab and co-first author of this study. These findings lead us to believe that OTUD5 may have far-reaching effects beyond those identified in LINKED patients.

In future work, Werners team plans to fully investigate the role which OTUD5 and similar enzymes play in development. The researchers hope the study can serve as a guiding framework for unraveling the causes of other undiagnosed diseases, ultimately helping clinicians better evaluate and care for patients.

Were finally able to provide families with a diagnosis, bringing an end to what is often a long and exhausting search for answers, said Beck.

Source:

Journal reference:

Beck, D.B.,et al.(2021) Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation.Science Advances.doi.org/10.1126/sciadv.abe2116.

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Scientists find uncommon hereditary disorder that influences the brain, heart and facial highlights - Microbioz India

Spinal Cord Stem Cells Comments Off on Scientists find uncommon hereditary disorder that influences the brain, heart and facial highlights – Microbioz India | January 25th, 2021

2021 objectives leverage positive momentum in Arbutus’ Hepatitis B research and development programs

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Arbutus Announces 2021 Corporate Objectives and Provides Financial Update

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Clinical trial amendment successfully completed for co-primary endpoints of partial wound closure and mean pain reduction Clinical trial amendment successfully completed for co-primary endpoints of partial wound closure and mean pain reduction

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Abeona Therapeutics Announces Successful Type B Meeting with FDA for Pivotal Phase 3 VIITAL™ Study of EB-101 in Recessive Dystrophic Epidermolysis...

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PRESS RELEASE

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Saniona received approximately USD $2.9 million (SEK 24.2 million) upfront payment in connection with Cadent Therapeutics transaction

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Poster highlights NRP2 expression on immune cells in the tumor microenvironment.

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aTyr Pharma Presents Findings Further Validating NRP2 as a Potential Regulator of Solid Tumor Progression

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SAN DIEGO, Jan. 25, 2021 (GLOBE NEWSWIRE) -- Cidara Therapeutics, Inc. (Nasdaq: CDTX), a biotechnology company developing long-acting therapeutics designed to transform the standard of care for patients facing serious fungal or viral infections, today announced the appointments of internationally-renowned molecular biologist Bonnie Bassler, Ph.D., and seasoned life science executive Carin Canale-Theakston to its board of directors.

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Cidara Therapeutics Announces Key Additions to its Board of Directors

Global News Feed Comments Off on Cidara Therapeutics Announces Key Additions to its Board of Directors | January 25th, 2021

- Company receives FDA Priority Review with PDUFA date set for July 20, 2021 -

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Albireo Announces U.S. FDA Acceptance of New Drug Application for Odevixibat

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Thought Leaders Will Advise BrightInsight as Demand Grows for its Regulated Digital Health SaaS Platform Thought Leaders Will Advise BrightInsight as Demand Grows for its Regulated Digital Health SaaS Platform

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BrightInsight Names Technology and Healthcare Leaders to Advisory Council

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Innovative Digital Commerce Veteran Joins Dynamic Sales Team Innovative Digital Commerce Veteran Joins Dynamic Sales Team

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Better Choice Company Appoints Jenny Condon as Executive Vice President of Digital Sales

Global News Feed Comments Off on Better Choice Company Appoints Jenny Condon as Executive Vice President of Digital Sales | January 25th, 2021

CAMBRIDGE, Mass., Jan. 25, 2021 (GLOBE NEWSWIRE) -- Vericel Corporation (NASDAQ:VCEL), a leader in advanced therapies for the sports medicine and severe burn care markets, announced the appointment of Joe Mara as Chief Financial Officer of the Company, effective today.

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Vericel Announces Appointment of Joe Mara as Chief Financial Officer

Global News Feed Comments Off on Vericel Announces Appointment of Joe Mara as Chief Financial Officer | January 25th, 2021

BASKING RIDGE, N.J., Jan. 25, 2021 (GLOBE NEWSWIRE) -- Caladrius Biosciences, Inc. (Nasdaq: CLBS) (“Caladrius” or the “Company”), a clinical-stage biopharmaceutical company dedicated to the development of cellular therapies designed to reverse disease, today announced its participation in the following virtual conferences in February.

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Caladrius Biosciences Announces Participation in Upcoming Virtual Conferences in February 2021

Global News Feed Comments Off on Caladrius Biosciences Announces Participation in Upcoming Virtual Conferences in February 2021 | January 25th, 2021

Balance Sheet Strengthened and also Announces Retention of Investor Relations Firm Balance Sheet Strengthened and also Announces Retention of Investor Relations Firm

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TORONTO, CHICAGO and MONTREAL, Jan. 25, 2021 (GLOBE NEWSWIRE) -- Medexus Pharmaceuticals Inc. (the “Company” or “Medexus”) (TSXV: MDP) (OTCQX: MEDXF) (Frankfurt: P731) announced today that it has renewed and expanded its distribution agreement for NYDA®, a market leading treatment for head lice, through September 26, 2026. The agreement with G. Pohl-Boskamp GmbH & Co KG ("Pohl-Boskamp") provides the Company with exclusive Canadian distribution rights for NYDA® and includes a commitment related to bringing new and innovative solutions to the Canadian market. The initial agreement with Pohl-Boskamp was signed in 2011 and the first extension was announced in June 2015.

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Medexus Announces Renewal and Expansion of Canadian Distribution Agreement for NYDA®

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