As interest in chimeric antigen receptor (CAR) T-cell therapy continues to grow with more promising data coming out and approvals from the FDA in various hematologic malignancies, the role of this cellular therapy has yet to be defined in multiple myeloma, but recent data have inspired hope for this therapy in the relapsed/refractory population.

The B-cell maturation antigen (BCMA)directed CAR T-cell therapy idecabtagene vicleucel (ide-cel; bb2121) has generated excitement in this population following the submission of a Biologics License Application (BLA) in March 2020, seeking approval of ide-cel in patients with multiple myeloma who have received at least 3 prior therapies, including an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and an anti-CD38 antibody, and a Priority Review designation granted in September 2020. Following delays in the review due to coronavirus disease 2019, the Prescription Drug User Fee Act action date has been set as March 27, 2021.

Deep and durable responses were observed with ide-cel as treatment of heavily pretreated patients with relapsed/refractory multiple myeloma, according to updated results from the CRB-401 study presented by Yi Lin, MD, PhD, assistant professor of oncology and associate professor of medicine at Mayo Clinic, during the 2020 American Society of Hematology (ASH) Annual Meeting. The efficacy and safety findings were consistent with prior findings and supported a favorable clinical risk-benefit profile at target dose levels 150 x 106.1

The median overall survival with ide-cel was 34.2 months (95% CI, 19.2-not evaluable) among all patients in this triple-classexposed population, and half of the patients who had ongoing responses achieved a duration of response >2 years. The median progression-free survival (PFS) was 8.8 months (95% CI, 5.9-11.9). The objective response rate (ORR) overall was 75.8%, which included complete responses (CRs) in 38.7%.

These results from CRB-401 are comparable to the findings from the pivotal phase 2 KarMMa study (NCT03361748), which were presented earlier this year during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program and support the Biologics License Application. The median OS for this study was 19.4 months, and the median PFS was 8.8 months. The ORR was 73%, which included a CR rate of 33%, and the median duration of response was 10.7 months.2

Ide-cel is being explored in several ongoing studies as well, including the phase 2 KarMMa-2 (NCT-3601078), phase 3 KarMMa-3 (NCT03651128), and phase 1 KarMMa-4 (NCT04196491) clinical trials. These phase 2 and 3 studies are evaluating ide-cel in patients with triple-classexposed disease, and the phase 1 study will explore the use of this CAR T-cell therapy in patients with high-risk newly diagnosed multiple myeloma.

These data have also set the stage for other BCMA-directed CAR T-cell therapies in development for the treatment of patients with multiple myeloma.

In an interview with Targeted Oncology, Lin discussed the updated findings from the CRB-401 study of ide-cel as treatment of patients with relapsed/refractory multiple myeloma.

TARGETED ONCOLOGY: What historical data have we seen with BCMA-directed CAR T-cell therapy in patients with relapsed/refractory multiple myeloma?

Lin: With the CAR T approach in multiple myeloma, the very first case report was actually with CD19-targeted CAR T because there was already experience with that particular antigen in leukemia and lymphomas. There's some ongoing effort in terms of dual targeting with CD19 and BCMA, but BCMA very quickly emerged as an ideal candidate for the myeloma space. This is an antigen that is more uniformly expressed on plasma cells, including myeloma cells, and maybe a small subset of mature B cells, but otherwise BCMA is not expressed on healthy tissues.

There have been some single-center clinical trials with the BCMA-targeted CAR T approach prior to the CRB-401 study, both with National Cancer Institute and the University of Pennsylvania with slightly different constructs. With those early phase 1 studies, there was a little bit more toxicity seen, although there was certainly some response, but the response wasn't particularly durable. CRB-401 is the first in a series of now industry-sponsored multicenter studies, in which we are now seeing a much more encouraging durable response rate and also a more favorable side effect profile as well. At ASH this year, I presented the longer follow-up on the phase 1 CRB-401 study. There is a pivotal phase 2 KarMMa study using the same CAR T construct that had been presented at ASCO earlier this year.

TARGETED ONCOLOGY: Please describe the design of the trial and what was different about the study.

Lin: The CRB-401 study has 2 parts. The first part is the dose-escalation part, and the second part is the dose expansion. The dose escalation is basically testing the range of a fixed dose of 50 million all the way up to 800 million of ide-cel CAR T cells in a relatively small number of patients, basically looking for signs of severe side effects to identify a safe dose. The dose expansion cohort is where we take the more promising doses in terms of response, and also safety profile, and test them in more patients to get a better safety signal, which is then moved forward for phase 2 testing in the KarMMa study.

In the dose-expansion portion of CRB-401, we required that each patient must have had exposure to an anti-CD38 antibody. That was allowed in a dose escalation but not required for everybody. [To be included in the study,] the patient must have had become refractory to the most recent line of treatment before they came on the study. The other thing that was different was that in the dose-escalation cohort, all patients had their myeloma cells in the bone marrow reviewed centrally by immunohistochemistry staining, and they were required to have at least 50% of these cells having BCMA expression in a dose-expansion cohort, to better understand the clinical efficacy and safety profiles of this treatment. We also included some patients that had BCMA expression below that to even levels that were not detectable by immunohistochemistry.

TARGETED ONCOLOGY: What were the results from this study?

Lin: The study [included] a total of 62 patients. The results from the first 33 patients were already published in the New England Journal of Medicine last year, and this year at ASH, data were presented for outcomes of the entire 62-patient cohort, with a median follow-up of now 18.1 months. What we have seen so far is in this entire treated patient cohort these are patients with very high-risk features of myeloma, and close to a third of these patients had high-risk cytogenetics, 37% of these patients had extra modularity plasma effect, and almost half of these patients needed some type of systemic therapy while their CAR T cells are being made. These patients, on average, had 6 lines of prior therapy, and in close to 70% or higher, these patients are either triple-refractory or were refractory to the most recent line of therapy.

For this group of patients that was treated overall, the safety signal was very tolerable, which is not surprising with CAR T therapy because these patients also do get lymphodepletion chemotherapy as part of the treatment with CAR T. We do see that low blood count is the most common side effect, including the more severe low blood counts, but on average, the recovery of these blood counts can be seen well under the first 3 months after CAR T infusion. The other most common side effects that we need to watch for with CAR T are cytokine release syndrome (CRS) and neurotoxicity. What we have seen in this study is that, on average, about 76% of these patients had some type of CRS. However, those that had grade 3 or higher, that is only [seen] in 6.5% of the patients, so much lower, and that's also reflected in the relative lower use of tocilizumab and steroids, as well, to manage the side effects. About 35% of these patients had some type of neurologic side effect, but again, only 1 patient had a more severe form of neurotoxicity. Compared to what we have seen with the CAR T experience in the lymphoma/leukemia space, this is a very, very encouraging safety profile.

We have also now seen that the ORR is quite high. It's 75.8% with a CR and stringent CR rate of about 38.7%. Many of these patients that had bone marrow that were evaluable for minimal residual disease (MRD) response were MRD-negative. We are seeing, since we tested many doses, that there is a dose-related increase in response with increasing [the] dose, and we have also seen that the duration of response is 10.3 months. When we look at the dose that was tested as well in those expansions [in] the 150 to 450 range, what we have seen is that the duration of response is comparable, so not significantly decreased, for patients with high-risk features like those with extramedullary disease for older patients, as well as patients who needed to get bridging therapy during treatment. The median PFS is 8.8 months, and the median OS is 34.2 months.

So far, the response rate, duration of response, and PFS seem to be comparable to what we also now see in the KarMMa study, which has less follow-up, but we are seeing a very nice median OS for a treatment in which we're just giving a 1 dose infusion and no follow-up maintenance therapy.

TARGETED ONCOLOGY: In terms of CAR T-cell therapy, how do you see this strategy impacting this patient population in the future?

Lin: I think there's definitely a role for this in the practice. The BLA for ide-cel has been submitted to the FDA, so we're anticipating review sometime in early 2021. This is very exciting because this could very well be the first CAR T for multiple myeloma. I think this would definitely be a treatment option for these patients. Based on how KarMMa is designed, we anticipate that the FDA approval will be in the space of patients who [have] had at least 3 lines of prior therapy and have been exposed to the currently approved 3 main backbones of treatmenta PI, IMiD, and the CD38 antibody. The full detail is pending final FDA review and the label. However, in that space, certainly looking at the demographic of the patient that's been treated so far as CRB-401 and KarMMa, that's a wider group of patients. Based on the fact that this is a treatment that is a basically living active cells, I perceive that the earlier that patient could get this therapy in the earliest possible approved indication, there would likely be potentially more benefit for the patients.

TARGETED ONCOLOGY: Do you think there is hope for this treatment in other hematologic malignancies outside of lymphomas and leukemias as well?

Lin: That is actually a very interesting question because what we're seeing in terms of the severity of CRS and neurotoxicity is a reflection of our evolving learning about how to manage the toxicity, as well. There is a component to the CAR design, the disease, the nature of the disease, the kinetics of the CAR T actions, in the manifestation of these symptoms. What we are seeing now, with even the prior CAR and next-generation CAR coming on, we will likely see an ongoing improvement in terms of a reduction of severity of these symptoms and also in the ways that we could manage these symptoms.

The fact that myeloma would be the next disease that has an FDA-approved CAR T also relates to the fact that the BCMA antigen is more restricted on the cell type where the malignancy is involved, similar to CD19 for lymphoid malignancy. We are seeing that there are some challenges, for example with acute myeloid leukemia or myeloid neoplasms where a number of antigens could overlap with stem cells, which we wouldn't want to try to hurt. There are some novel CAR approaches to try to overcome that, and those are in very early phase testing, so we'll need to see how those results evolve.

References

1. Lin Y, Raje NS, Berdeja JG, et al. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy, in patients with relapsed and refractory multiple myeloma: updated results from phase 1 CRB-401 study. Presented at: 2020 ASH Annual Meeting & Exposition; December 5-8, 2020; Virtual. Abstract 131.

2. Munshi NC, Anderson Jr LD, Jagannath S, et al. Idecabtagene vicleucel (ide-cel; bb2121), a BCMA-targeted CAR T-cell therapy, in patients with relapsed and refractory multiple myeloma (RRMM): Initial KarMMa results.J Clin Oncol. 2020;38(suppl):8503. doi:10.1200/JCO.2020.38.15_suppl.8503

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Updated Findings Show Continued Efficacy for CAR T-Cell Therapy in Heavily Pretreated Myeloma - Targeted Oncology

Bone Marrow Stem Cells Comments Off on Updated Findings Show Continued Efficacy for CAR T-Cell Therapy in Heavily Pretreated Myeloma – Targeted Oncology | December 14th, 2020

The allogeneic off-the-shelf CD22-directed T-cell product, UCART22, showed early signs of activity and no evidence of unexpected toxicities at 2 dose levels for adult patients with relapsed/refractory CD22-positive B-cell acute lymphoblastic leukemia, according to the results of a study presented during the 2020 ASH Annual Meeting.1

In the phase 1 BALLI-01 (NCT04150497) dose-escalation and dose-expansion study, 2 patients at the 1 x 105 cells/kg dose achieved a complete remission (CR) with incomplete hematologic recovery on day 28. One of these patients attained a minimal residual disease (MRD)positive CR at day 42 followed by subsequent inotuzumab ozogamicin (Besponsa) and then transplant.

One patient at dose level 2, 1 x 106 cells/kg, experienced a significant bone marrow blast reduction at day 28, followed by disease progression.

No patients experienced dose-limiting toxicities (DLTs), immune effector cellassociated neurotoxicity syndrome (ICANS), graft-versus-host disease (GVHD), adverse effects (AE) of special interest (AESI), a UCART22-related AE that was grade 3 or higher, or a serious AE (SAE).

UCART22 showed no unexpected toxicities at the doses of 1 x 105 cells/kg and 1 x 106 cells/kg with fludarabine and cyclophosphamide lymphodepletion, lead study author Nitin Jain, MD, an assistant professor in the Department of Leukemia, The University of Texas MD Anderson Cancer Center, said in a virtual presentation during the meeting. Host immune recovery was observed early, and the addition of alemtuzumab [Lemtrada] to fludarabine and cyclophosphamide lymphodepletion is currently being explored with the goal to achieve deeper and more sustained T-cell depletion and to promote expansion and persistence of UCART22.

Standard treatment for adult patients with B-cell ALL includes multiagent chemotherapy with or without allogeneic stem cell transplant. However, 30% to 60% of patients with newly diagnosed B-cell ALL who achieve a CR will relapse, and the expected 5-year survival rate for those with relapsed/refractory disease is approximately 10%.

Previously, UCART19, when paired with lymphodepletion using fludarabine, cyclophosphamide, and alemtuzumab, was found to show efficacy in this patient population.2

CD22 is an FDA-approved therapeutic target in B-cell ALL. UCART22 is an immediately available, standardized, manufactured agent with the ability to re-dose, and its CAR expression redirects T cells to tumor antigens, Jain explained.

Moreover, through its mechanism of action, TRAC becomes disrupted using Transcription activator-like effector nucleases (Talen) technology to eliminate TCR from cell surface and reduce the risk of GVHD. CD52 is also disrupted with the use of Talen to eliminate sensitivity to lymphodepletion with alemtuzumab. Finally, there is a CD20 mimotope for rituximab (Rituxan) as a safety switch, Jain added.

UCART22 has also demonstrated in vivo antitumor activity in immune-compromised mice that were engrafted with CD22-positive Burkitt lymphoma cells in a dose-dependent manner.

In the dose-escalation/dose-expansion BALLI-01 study, investigators are enrolling up to 30 patients in a modified Toxicity Probability Interval design. There are 3 cohorts, which have 2 to 4 patients on each cohort: 1 x 105 cells/kg (dose level 1), 1 x 106 cells/kg (dose level 2), and 5 x 106 cells/kg. The focus of the dose-escalation phase of the trial was to determine the maximum-tolerated dose (MTD) and the recommended phase 2 dose (RP2D) before heading into the dose-expansion portion of the trial.

To be eligible for enrollment, patients must have been between 18 and 70 years old, have acceptable organ function, an ECOG performance status of 0 or 1, at least 90% of B-cell ALL blast CD22 expression, and had previously received at least 1 standard chemotherapy regimen and at least 1 salvage regimen.

End points of the trial included safety and tolerability, MTD/R2PD, investigator-assessed response, immune reconstitution, and UCART22 expansion and persistence.

The lymphodepletion regimens were comprised of fludarabine (at 30 mg/m2 x 4 days) plus cyclophosphamide (1 g/m2 x 3 days); the study has since been amended to include the regimen of fludarabine (at 30 mg/m2 x 3 days), cyclophosphamide (500 g/m2 x 3 days), and alemtuzumab (20 mg/day x 3 days) and is currently enrolling patients.

Following screening, lymphodepletion, and UCART22 infusion, patients underwent an observation period for DLTs with a primary disease evaluation at 28 days; additional efficacy evaluations occurred at 56 days and 84 days. Patients were followed for 2 years and continued to be assessed for long-term follow-up.

As of July 1, 2020, 7 patients were screened, of which 1 patient failed and 6 were therefore enrolled on the study. One patient discontinued therapy before receiving UCART22 due to hypoxia from pneumonitis that was linked with lymphodepletion. Five patients were treated with UCART22 at dose level 1 (n = 3) and dose level 2 (n = 2).

The median age of participants was 24 years (range, 22-52), 3 of the 5 patients were male, and 3 had an ECOG performance status of 0. The median number of prior therapies was 3 (range, 2-6), and there were a median 35% bone marrow blasts (range, 10%-78%) prior to lymphodepletion.

Three patients had complex karyotype and 2 had diploid cytogenetics. One patient each had the following molecular abnormalities: CRLF2, CRLF2 and JAK2, CDKN2A loss, KRAS and PTPN11, and IKZF1. Only 1 patient had undergone haploidentical transplant. Four patients previously received prior CD19- or CD22-directed therapy, including blinatumomab (Blincyto), inotuzumab ozogamicin (Besponsa), and CD19-directed CAR T-cell therapy. At study entry, 3 patients had refractory disease and 2 patients had relapsed disease.

Grade 3 or higher treatment-emergent AEs (TEAEs), which were unrelated to study treatment, included hypokalemia, anemia, increased bilirubin, and acute hypoxic respiratory failure. Also not related to UCART22, 3 patients experienced 4 treatment-emergent SAEs: porta-hepatis hematoma, sepsis, bleeding, and sepsis in the context of disease progression. No treatment discontinuations due to a treatment-related TEAE were reported.

The patient who achieved a CR followed by transplant was a 22-year-old male who had undergone 2 prior treatments for B-cell ALL and received UCART22 at a dose of 1 x 105 cells/kg. He did not experience CRS, ICANS, GVHD, nor a SAE, and all TEAEs were grade 1.

Jain also noted that host T-cell constitution was observed in all patients within the DLT observation period. UCART22 was also not detectable through flow cytometry or molecular analysis, the latter of which was at dose level 1 only.

References:

1. Jain N, Roboz GJ, Konopleva M, et al. Preliminary results of BALLI-O1: a phase I study of UCART22 (allogeneic engineered T cells expressing anti-CD22 chimeric antigen receptor) in adult patients with relapsed/refractory anti-CD22+ B-cell acute lymphoblastic leukemia (NCT04150497). Presented at: 2020 ASH Annual Meeting and Exposition; December 4-8, 2020; Virtual. Abstract 163.

2. Benjamin R, Graham C, Yallop D, et al. Preliminary data on safety, cellular kinetics and anti-leukemic activity of UCART19, an allogeneic anti-CD19 CAR T-cell product, in a pool of adult and pediatric patients with high-risk CD19+ relapsed/refractory b-cell acute lymphoblastic leukemia. Blood. 2018;132(suppl 1):896. doi:10.1182/blood-2018-99-111356.

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Early Signs of Activity and Tolerability Found in Allogeneic Product UCART22 for Patients with Relapsed/Refractory CD22+ B-Cell ALL - Cancer Network

Bone Marrow Stem Cells Comments Off on Early Signs of Activity and Tolerability Found in Allogeneic Product UCART22 for Patients with Relapsed/Refractory CD22+ B-Cell ALL – Cancer Network | December 14th, 2020

The Covid-19 can damage the heart both directly and indirectly, and lead to complications ranging from inflammation of the heart (myocarditis), injury to heart cells (necrosis), heart rhythm disorders (arrhythmias), heart attack, and muscle dysfunction that can lead to acute or protracted heart failure, experts said.

Covid-19 is a vascular disease that injures heart cells and muscle. It also leads to the formation of blood clots, both in the microvasculature and large vessels, which can block blood supply to the heart, brain and lungs and lead to stroke, heart attack and respiratory failure, said Dr Ravi R Kasliwal, chairman of clinical and preventive cardiology department at Medanta -The Medicity Hospital.

Also Read: Few Covid-19 deaths in Indias old-age homes, survey finds

A US study using MRI found cardiac abnormalities in 78 of 100 patients who had recently recovered from Covid-19, including 12 of 18 asymptomatic patients. Sixty patients had ongoing myocardial inflammation consistent with myocarditis, found the study, which was published in the Journal of American Medical Association Cardiology in July.

Even people with mild disease or no symptoms can develop life-threatening cardiovascular complications. Whats worrying is that this holds true for healthy adults with no pre-existing risk factors, which raise their risk of complications, said Dr Kasliwal, who recommends that everyone who has recovered from Covid-19 be screened for heart damage

Cardiac trouble

Extensive cardiac involvement is what differentiates Sars-CoV-2, the virus that causes Covid-19, from the six other coronaviruses that cause infection in humans, writes cardiologist Dr Eric J Topol, founder, director and professor of molecular medicine at the Scripps Research Translational Institute in La Jolla, California, in the journal Science.

The four human coronaviruses that cause cold-like symptoms have not been associated with heart abnormalities, though there have been isolated reports linking the Middle East Respiratory Syndrome (MERS) caused by MERS-CoV) with myocarditis, and cardiac disease with the Severe Acute Respiratory Syndrome (SARS) caused by Sars-CoV.

Also Read| Extraordinary uncertainties: Harvard prof on Covid-19, impact on mental health

Sars-CoV-2 is structurally different from Sars-CoV. The virus targets the angiotensin-converting enzyme 2 (Ace2) receptor throughout the body, facilitating cell entry by way of its spike protein, along with the cooperation of proteases. The heart is one of the many organs with high expression of Ace2. The affinity of Sars-CoV-2 to Ace2 is significantly greater than that of SARS, according to Dr Topol.

Topol notes the ease with which Sars-CoV-2 infects heart cells derived from induced pluripotent stem cells (iPSCs) in vitro, leading to a distinctive pattern of heart muscle cell fragmentation evident in autopsy reports. Besides directly infecting heart muscle cells, Sars-CoV-2 also enters and infects the endothelial cells that line the blood vessels to the heart and multiple vascular beds, leading to a secondary immune response. This causes blood pressure dysregulation, and activation of a proinflammatory response leading to a cytokine storm, which is a potentially fatal systemic inflammatory syndrome associated with Covid-19.

Persisting problems

Studies have found that injury to heart cells reflected in blood concentrations of a cardiac muscle-specific enzyme called troponin affects at least one in five hospitalised patients and more than half of those with pre-existing heart conditions, which raises the risk of death. Patients with higher troponin amounts also have high markers of inflammation (including C-reactive protein, interleukin-6, ferritin, lactate dehydrogenase), high neutrophil count, and heart dysfunction, all of which heighten immune response.

The heightened systemic inflammatory responses and diminished blood supply because of clotting, endotheliitis (blood vessel inflammation), sepsis, or hypoxemia (oxygen deprivation) because of acute lung infection leads to indirect cardiac damage, said Dr Kasliwal.

The cardiovascular damage associated with Sars-CoV-2 infection can persist beyond recovery. Since the virus affects the heart as much as the respiratory tract, further research is needed to understand why some people are more vulnerable to heart damage than others.

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Covid-19 can have impact on heart too, say experts - Hindustan Times

Cardiac Stem Cells Comments Off on Covid-19 can have impact on heart too, say experts – Hindustan Times | December 14th, 2020

Asian beauty woman putting on mask on face. Wearing corona virus prevention masks for long hours are ... [+] creating irritation, skin problems, acne pimples.

Its starts with a seemingly harmless blackhead. Then you notice redness and swelling that will inevitably birth a dreaded pimple. The next thing you know one zit has multiplied to cover almost an entire area of your face along the jawline or chin. Like most skin breakouts, once acne takes over your life, it will often feels like a losing battle.

My bout with acne took over three months of my quarantine life with wounds (okay, maybe scars is a better word for it) that remind me to never again take this skin pandemic lightly. The guesswork was tedious and for weeks seemed futile. There were trial and error attempts, in search of a balancing skincare routine that would clear skin without stripping it off its moisture. This is most important especially for those with combination skin. I even cheated on my trusted dermatologist, only to get a subpar facial that did nothing to improve skins condition. Said facialist, however, offer sound advice: Forego products that will leave your skin oily until the acne has subsided. This will take a while.

Before getting into the meaty details of this war against maskne, lets talk about causes. Maskne is basically acne brought about by wearing face masks for prolonged periods of time. Heat, dirt, sweat and bacteria, when covered by fabrics or other materials used to make face coverings, trigger skin flare ups. Even in cooler temperature, maskne continues to be a bane especially for sensitive skin thats dry and flaky. So yes, the war is far from over, but the good news is it can be won.

A GENTLE AND THOROUGH SKIN CLEANSE is your first step to beating this very frustrating skin condition. I looked far and wide for natural cleansers that would help to control the oil, sebum and dirt. Oil-based cleansers seemed to aggravate the flare up. Bar soaps left skin feeling tight, dry and flaky. Clean facial wash formulations with tea tree oil work wonders as an anti-microbial skin solution. Of the many choices on offer, an all-natural Philippine made Acne Defense Facial Wash from HUMAN NATURE fulfilled its promise of soothing a nasty flare up without drying skin.

Alpyn Beauty's Wild Huckleberry 8-Acid Polishing Peel

Alypn Beauty's Wildhuckleberry 8 Acid Polishing Peel is a multitasking skin treat that works as a ... [+] mask, skin peel and polish.

After a refreshing facial wash, double cleanse with an ultra gentle, multitasking mask, peel and scrub and polish in a jar. ALPYN BEAUTYs Wild Huckleberry 8-Acid Polishing Peel has sold out several times since it launched in Octoberand for good reason. This skin treat harnesses the powers of a natural salicylic, citric, malic, tartaric, glycolic, azelac, ferulic and lactic acids to exfoliate skin and dissolve dead skin cells. Wild crafted huckleberry protects skin barrier, while bamboo power combined with blueberry seed paste effect natural microdermabrasion of skin. This light and delicious skin peel is so gentle you can use is daily, day and night. Ingredients used for this heaven-sent are all sustainably sourced and wild-crafted so you know that it does your skin, soul and planet good. This peel is also ideal for prepping skin before makeup application.

M-61 Power Glow Toner exfoliates away impurities, refine pores, and smoothens skin texture to ... [+] prevent blemishes and quickly improve existing acne

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ZITSTICKA's Press Refresh Sheet Mask combines functional technology and skincare tailored to fight ... [+] acne. It is formulated with salicylic acid, glycolic acid, lactic acid, Niacinamide (to calm) and vitamin A.

Skin flare ups and breakouts in the past have taught me that the first thing to go when pimples take over are heavy creams and moisturizers. As much as we all love a good dose of hydration, war against maskne calls for heavy reinforcements like a hardworking, skin saving face mask. ZITSTICKAs Press Refresh Hydrogel Sheet Mask is a warrior that combines functional technology and skincare tailored to fight acne. It is formulated with salicylic acid, glycolic acid, lactic acid, Niacinamide (to calm) and vitamin A.

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Peace Out Healing Dots combine Hydrocolloid, Salicylic Acid, Vitamin A and Aloe Vera to clear up ... [+] acne-causing bacteria and reduce redness overnight.

Peace Out Acne Serum is formulated with Salicylic Acid, Niacinamide, Vitamin C & Zinc that work ... [+] together to clear blemishes, prevent them from returning

Maskne is stubborn and often requires a stroke of mad brilliance to beat. PEACE OUT, the leading anti acne skincare brand at Sephora, has changed the way we address breakouts with a full range of innovative skincare solutions. The Acne Healing Dot combines hydrocolloid polymer technology with clean, active ingredients to zap zits. Instead of applying gel or liquid formulas on the surface, PEACE OUT offers fun, stick on skin solutions for hardcore breakouts. I had to try it to believe. To use, simply apply the sticker directly on the affected areas and leave on for a couple of hours. Hydrocolloid dressings absorb moisture and toxins trapped underneath the skins surface, which effectively helps to reduce redness and swelling. Use of this technology also helps to speed up healing of acne. For best results, pair the Healing Dots with PEACE OUTs Acne Serum. Salicylic acid infused with Niacinamide and Vitamin C decongests pores, while reducing the appearance of dark spots and blemishes.

Heraux Molecular Anti-Inflammaging Serum shielding stem cells from the effects of stress and ... [+] promotES their overall youthful function.

Its also essential that you give skin the protective barrier it needs against stressors and irritants. This helps to form a layer that will keep it from inflammation and ultimately, breakouts. HERAUX Molecular Anti Inflammaging Serum uses the first and proprietary Biomimetic Lipid, HX-1, to target inflammaging or aging caused by inflammation. Through the discovery of two stem cell scientists, this breakthrough skincare formulation shields stem cells from the effects of stress and promotes their overall youthful function by modulating the protein that regulates regeneration versus inflammation. The layer has also helped me to protect skin and bring back its radiance and texture.

Ive been using Heraux for a month now, applying a pea-sized amount on thoroughly cleansed skin before getting on with my day. This potent, light serum leaves a matte finish on skin which is brilliant especially when you are paring down on makeup. Pores appear smaller and more importantly, skin barrier is less likely to react to friction or contact with face coverings. After a few weeks of continued use, skin was visibly more youthful and refreshed.

Femmue Lumiere Vital C Serum to help lighten post acne blemishes and dark spots.

Gradually bring back skin hydration into your routine with FEMMUE Ideal Creme Riche

Dull and dry skin with are some of the after effects of a maskne breakout. You can also expect unsightly blemishes and dark spots. To revive clear, smooth and radiant skin, FEMMUEs flower therapy serums and mask did not disappoint. Using modern botanicals, products like Lumiere Vital C Serum and Ideal Cream Riche are skin super healers that restore skins glow and texture. Lumiere is a multi-tasking lightweight formula that works as both an antioxidant and brightening solution. It stimulates collagen production while refining skin surface and lightening dark spots. It is also specially formulated to work beautifully with extra sensitive, acne-prone skin types. For a restorative nighttime skincare routine, pair this serum with FEMMUEs Ideal Crme Riche every other night. Apply a very thin layer all over your face, making sure to tap excess cream with facial tissue. I love to follow with a 10-minute LED Face Mask session just before dozing off.

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The best way to keep maskne from taking over your life again is to choose invest in a an antibacterial, breathable face mask. I love a stylish statement masks and have built quite a collection over the months. For long days that will require hours of wear, however, opt for cotton face masks that allow skin to breathe. Infusion of copper and metal ions into the fabric also help to fight off bacteria. SCELIDO Nano Antibacterial and Antivirus Cooling Mask uses ASKIN and Aero Silver fabric, which gives 99.9% antibacterial and UV protection. It is as effective in protecting wearers from viruses as a KF80 but is light, breathable, reusable and effective in preventing acne. Copper threads enhances protection level and seamless ergonomic design (with sizing from XS to Large) allows this facial covering to sit perfectly on skin without causing traction and irritation.

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A Tried And Tested Guide On How To Win The War Against Maskne - Forbes

Skin Stem Cells Comments Off on A Tried And Tested Guide On How To Win The War Against Maskne – Forbes | December 13th, 2020

Author Thomas Thompson once characterized Houston circa 1945 as a city where medicine of the most mediocre sort was practiced, a city with a third-rate medical school, no heritage of scholarly thinking and where extinguishing life by violence was far more common than exploring methods to prolong it.

That all changed in less time than it takes to age a good bottle of wine, according to the author of the true crime classic Blood and Money.

In a swampy area six miles south of the heart of downtown, in fields where racoons and water moccasins lived, there sprang up a collection of medical facilities which, by 1970, had become one of the handful of distinguished medical centers in the world, Thompson wrote in Hearts: Of Surgeons and Transplants, Miracles and Disasters Along the Cardiac Front.

No one was more responsible for the transformation, of course, than Michael DeBakey and Denton Cooley, the pioneering surgeons whose innovations made Houston and the Texas Medical Center the epicenter for cardiovascular care, a place where the most cutting-edge therapies were practiced with the greatest skill, a place that drew patients from around the nation and world, both common man and heads of state.

The advances culminated in Cooley implanting the worlds first artificial heart in a person, a dream since the 1940s, a Kitty Hawk type of advance. The story made headlines around the world and, even though the device was never used again, its legacy can be seen in the mechanical cardiac parts people now take for granted valves, pacemakers and, most of all, support devices that help diseased hearts better pump blood.

But the achievements started long before that. In medical school. DeBakey invented the so-called roller pump, which made it possible to provide a surgical patient with a continuous flow of blood. DeBakeys invention would would become the essential component of the heart-lung machine that maintained the patients vital functions during procedures, ushering in the era of open heart surgery.

In 1952, DeBakey performed the first successful operation on an aneurysm a ballooning of the arterial wall by replacing the affecting area with a graft from a cadaver artery. The following year he performed the first successful surgery to remove blood clots and plaque from the inner lining of blood vessels that deliver blood to the brain and head, an advance that would go on to spare countless patients from devastating strokes.

Indeed, though DeBakey was known mostly as a heart surgeon, many experts consider such vascular procedures his greatest achievement. He made the aorta, the vessel that carries blood from the heart throughout the body, a treatable entity. Until then, aortic aneurysms and tears, were almost universally fatal.

Around that time, DeBakey created the first Dacron grafts one of the Texas Medical Centers great stories which enabled durable repair of artery walls weakened by aneurysms. He invented the technique on his wifes sewing machine using the then new material, bought at Foleys in downtown Houston when they were out of nylon and vinyon, the fabrics he preferred. He soon determined Dacron was superior because it didnt degenerate over time.

The role of Providence in human endeavor is speculative, but I like to think that in a personal case it was purposeful, DeBakey wrote in the American Surgeon in 2008. Obviously, because of my good fortune, I was ahead of everyone else in the field.

The invention, one of more than 50 he devised to repair hearts and arteries, won DeBakey the 1963 Lasker Award, the top American award in medicine.

The following year, while attempting a surgery that proved too difficult to complete, Dr. DeBakey improvised a coronary bypass procedure only previously performed successfully in dogs. In so doing, he became the first surgeon to perform a successful coronary bypass on a human patient.

In 1968, DeBakey was credited with the first simultaneous, multi-organ transplant, overseeing a team that removed the heart, lobe of one lung and both kidneys from a 20-year-old victim of a gunshot wound. The organs were transplanted into four patients: a 50-year-old man got the heart; a 39-year man got the partial lung; and two men, 41 and 22, each received a kidney.

Meanwhile, Cooley focused on hearts, performing an estimated 65,000 over four decades, more than any other surgeon. At one time, his surgical team was performing one-tenth of all open heart surgeries in the U.S.

Cooley stood above all others because of his speed and dexterity, a combination that produced what was described at the time as Woolworth volume and Tiffany qualtiy. He was quoted saying he always wanted to be known as the Sam Walton of heart surgery, in reference to the founder of Walmart.

MORNING REPORT: Get the top stories on HoustonChronicle.com sent directly to your inbox

But Cooley also pushed the boundaries of heart surgery. Dr. Christian Baarnard in South Africa beat him to the first heart transplant in December 1967, but Cooley matched the achievement five months later and his patient went on to live 204 days, compared to 18 for Baarnards patient.

In 1969, Cooley stunned the world by implanting a mechanical heart into the chest of Haskell Karp, a printing estimator in the last stages of heart failure. The device worked long enough to replace it with a donor heart when one became available three days later, although Karp died 32 hours later of pneumonia and kidney failure.

For all the attention it generated, the event didnt set off a wave of implants across the nation, the technology considered premature, rejection issues not yet well understood. Instead, it focused attention on alternatives known as left ventricular assist devices (LVADs), which assist the chamber that pumps blood throughout the body replace the heart. The approach was pioneered by DeBakey after he abandoned research into the total artificial heart.

Also pioneered in Houston: a minimally invasive procedure to replace a failing heart valve. The surgery, which entails threading the new valve to the heart through a blood vessel in the patients groin rather than open-heart surgery, was approved first for patients too sick and frail for open-heart surgery, then for patients at intermediate risk. More recently, studies showed it proved better than open surgery in young, healthy patients.

Houston doctors are at forefront of the next great hope for cardiovascular care too: regenerative medicine. The field is based on the idea that stem cells found in early stage embryos and adults, prized for their ability to easily divide and develop into various types of cells may be able to repair injuries and degeneration to heart tissue, an idea first tested at Texas Heart Institute around 2000. Though still a work in progress, the idea is considered the next frontier.

todd.ackerman@chron.com

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Houston healthcare in 1945 was 'mediocre.' The rivalry between DeBakey and Cooley changed it forever - Houston Chronicle

Cardiac Stem Cells Comments Off on Houston healthcare in 1945 was ‘mediocre.’ The rivalry between DeBakey and Cooley changed it forever – Houston Chronicle | December 13th, 2020

New York, Dec 12 (IANS) Researchers have revealed the appealing array of fruit and candy flavours that entice millions of young people to take up vaping are cardiotoxic and disrupt the heart's normal electrical activity.

Mounting studies indicate that the nicotine and other chemicals delivered by vaping, while generally less toxic than conventional cigarettes, can damage the lungs and heart.

"But so far there has been no clear understanding about what happens when the vaporized flavouring molecules in flavoured vaping products, after being inhaled, enter the bloodstream and reach the heart," said study author Sami Noujaim from the University of South Florida in the US.

In the study, published in the American Journal of Physiology-Heart and Circulatory Physiology, the research team reported on a series of experiments assessing the toxicity of vape flavourings in cardiac cells and in young mice.

The flavoured electronic nicotine delivery systems widely popular among teens and young adults are not harm-free.

"Altogether, our findings in the cells and mice indicate that vaping does interfere with the normal functioning of the heart and can potentially lead to cardiac rhythm disturbances," Noujaim said.

In mouse cardiac muscle cells (HL-1 cells), the researchers tested the toxicity of three different popular flavours of e-liquid: fruit flavour, cinnamon, and vanilla custard.

All three were toxic to HL-1 cells exposed to e-vapour bubbled into the laboratory dish where the cells were cultured.

Cardiac cells derived from human pluripotent stem cells were exposed to three distinct e-vapours.

The first e-vapour containing the only solvent interfered with the electrical activity and beating rate of cardiac cells in the dish. A second e-vapour with nicotine added to the solvent increased the toxic effects on these cells.

The third e-vapour comprised of nicotine, solvent, and vanilla custard flavouring (the flavour previously identified as most toxic) augmented damage to the spontaneously beating cells even more.

"This experiment told us that the flavouring chemicals added to vaping devices can increase harm beyond what the nicotine alone can do," Noujaim said.

The findings showed that mice exposed to vaping were more prone to an abnormal and dangerous heart rhythm disturbance known as ventricular tachycardia compared to control mice.

"Our research matters because regulation of the vaping industry is a work in progress," Noujaim noted.

--IANS

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Flavours added to vaping devices can damage the heart: Study - Sify News

Cardiac Stem Cells Comments Off on Flavours added to vaping devices can damage the heart: Study – Sify News | December 13th, 2020

Abstract

Enzyme replacement therapy, in which a functional copy of an enzyme is injected either systemically or directly into the brain of affected individuals, has proven to be an effective strategy for treating certain lysosomal storage diseases. The inefficient uptake of recombinant enzymes via the mannose-6-phosphate receptor, however, prohibits the broad utility of replacement therapy. Here, to improve the efficiency and efficacy of lysosomal enzyme uptake, we exploited the strategy used by diphtheria toxin to enter into the endolysosomal network of cells by creating a chimera between the receptor-binding fragment of diphtheria toxin and the lysosomal hydrolase TPP1. We show that chimeric TPP1 binds with high affinity to target cells and is efficiently delivered into lysosomes. Further, we show superior uptake of chimeric TPP1 over TPP1 alone in brain tissue following intracerebroventricular injection in mice lacking TPP1, demonstrating the potential of this strategy for enhancing lysosomal storage disease therapy.

Lysosomal storage diseases (LSDs) are a group of more than 70 inherited childhood diseases characterized by an accumulation of cellular metabolites arising from deficiencies in a specific protein, typically a lysosomal hydrolase. Although each individual disease is considered rare, LSDs have a combined incidence of between 1/5000 and 1/8000 live births, and together, they account for a substantial proportion of the neurodegenerative diseases in children (1). The particular age of onset for a given LSD varies depending on the affected protein and the percentage of enzymatic activity still present; however, in most cases, symptoms manifest early in life and progress insidiously, affecting multiple tissues and organs (2). In all but the mildest of cases, disease progression results in severe physical disability, possible intellectual disability, and a shortened life expectancy, with death occurring in late childhood or early adolescence.

As they are monogenic diseases, reintroducing a functional form of the defective enzyme into lysosomes is in principle a viable strategy for treating LSDs. Enzyme replacement therapy (ERT) is now approved for the treatment of seven LSDs, and clinical trials are ongoing for five others (3). However, delivering curative doses of recombinant lysosomal enzymes into lysosomes remains a major challenge in practice. ERT typically takes advantage of a specific N-glycan posttranslational modification, mannose-6-phosphorylation (M6P), which controls trafficking of endogenous lysosomal enzymes, as well as exogenous uptake of lysosomal enzymes from circulation by cells having the cation-independent M6P receptor (CIMPR) (4). Hence, a combination of factors including (i) the abundance of the M6P receptor in the liver, (ii) poor levels of CIMPR expression in several key target tissue types such as bone and skeletal muscle, (iii) incomplete and unpredictable M6P labeling of recombinant enzymes, and (iv) the highly variable affinity of recombinant lysosomal enzymes for CIMPR [viz., Kds (dissociation constants) ranging from low to mid micromolar (5, 6)] all contribute to diminishing the overall effectiveness of therapies using CIMPR for cell entry (3).

To improve the delivery of therapeutic lysosomal enzymes, we drew inspiration from bacterial toxins, which, as part of their mechanism, hijack specific host cellsurface receptors to gain entry into the endolysosomal pathway. While we and others have explored exploiting this pathway to deliver cargo into the cytosol (7, 8), here we asked whether this same approach could be used to enhance the delivery of lysosomal enzymes into lysosomes. We choose the diphtheria toxin (DT)diphtheria toxin receptor (DTR) system owing to the ubiquitous nature of the DTR, in particular its high expression levels on neurons.

Corynebacterium diphtheriae secretes DT exotoxin, which is spread to distant organs by the circulatory system, where it affects the lungs, heart, liver, kidneys, and the nervous system (9). It is estimated that 75% of individuals with acute disease also develop some form of peripheral or cranial neuropathy. This multiorgan targeting results from the fact that the DTR, heparin-binding EGF (epidermal growth factor)like growth factor (HBEGF), is ubiquitously expressed. The extent to which DT specifically targets difficult-to-access tissues such as muscle and bone, however, is not currently known.

DT is a three-domain protein that consists of an N-terminal ADP (adenosine diphosphate)ribosyl transferase enzyme (DTC), a central translocation domain (DTT), and a C-terminal receptorbinding domain (DTR). The latter is responsible for both binding cell surface HBEGF with high affinity [viz., Kd = 27 nM (10)] and triggering endocytosis into early endosomes (Fig. 1A). Within endosomes, DTT forms membrane-spanning pores that serve as conduits for DTC to enter the cytosol where it inactivates the host protein synthesis machinery. The remaining portions of the toxin remain in the endosomes and continue to lysosomes where they are degraded (11, 12). We hypothesized that the receptor-binding domain, lacking any means to escape endosomes, would proceed with any attached cargo to lysosomes and, thus, serve as a means to deliver cargo specifically into lysosomes following high-affinity binding to HBEGF.

(A) DT intoxication pathway (left), DT domain architecture, and LTM structure (right). (B and C) DTK51E/E148K, LTM, mCherry-LTM, and LTM-mCherry compete with wild-type DT for binding and inhibit its activity in a dose-dependent manner with IC50 (median inhibitory concentration) values of 46.9, 10.1, 52.7, and 76.1 nM, respectively (means SD; n = 3). (D and E) C-terminal and N-terminal fusions of LTM to mCherry were immunostained (red) and observed to colocalize with the lysosomal marker LAMP1 (39). (F) Fractional co-occurrence of the red channel with the green channel (Manders coefficient M2) were calculated for mCherry-LTM and LTM-mCherry and were found to be 0.61 0.10 and 0.52 0.11, respectively (means SD; n = 6).

In this study, we generated a series of chimeric proteins containing the DTR-binding domain, DTR, with the goal of demonstrating the feasibility of delivering therapeutic enzymes into lysosomes through the DT-HBEGF internalization pathway. We showed that DTR serves as a highly effective and versatile lysosome-targeting moiety (LTM). It can be placed at either the N or C terminus of the cargo, where it retains its high-affinity binding to HBEGF and the ability to promote trafficking into lysosomes both in vitro and in vivo. On the basis of its advantages, over M6P-mediated mechanisms, we further investigated the utility of LTM for the lysosomal delivery of human tripeptidyl peptidase-1 (TPP1) with the long-term goal of treating Batten disease.

To evaluate whether the DTR-binding fragment could function autonomously to traffic cargo into lysosomes, we first asked whether the isolated 17-kDa DTR fragment could be expressed independently from DT holotoxin and retain its affinity for HBEGF. We cloned, expressed, and purified the receptor-binding fragment and evaluated its ability to compete with full-length DT for the DTR, HBEGF. Before treating cells with a fixed dose of wild-type DT that completely inhibits protein synthesis, cells were incubated with a range of concentrations of LTM or a full-length, nontoxic mutant of DT (DTK51E/E148K). LTM-mediated inhibition of wild-type DT-mediated toxicity was equivalent to nontoxic DT (Fig. 1B), demonstrating that the receptor-binding fragment can be isolated from the holotoxin without affecting its ability to fold and bind cell surface HBEGF. Next, we evaluated whether LTM had a positional bias (i.e., was able to bind HBEGF with a fusion partner when positioned at either terminus). To this end, we generated N- and C-terminal fusions of LTM to the model fluorescent protein mCherry (i.e., mCherry-LTM and LTM-mCherry). To determine binding of each chimera to HBEGF, we quantified the ability of each chimera to compete with wild-type DT on cells in the intoxication assay. Both constructs competed with wild-type DT to the same extent as LTM alone and DTK51E/E148K (Fig. 1C), demonstrating that LTM is versatile and autonomously folds in different contexts.

To evaluate intracellular trafficking, HeLa cells were treated with either LTM-mCherry or mCherry-LTM and then fixed and stained 4 hours later with an antibody against the lysosomal marker LAMP1. In both cases, we observed significant uptake of the fusion protein (Fig. 1, D and E). We calculated Manders coefficients (M2) to quantify the extent to which signal in the red channel (LTM-mCherry and mCherry-LTM) was localizing with signal in the green channel (LAMP1). The fraction of red/green co-occurrence was calculated to be 0.61 for mCherry-LTM and 0.52 for LTM-mCherry, indicating trafficking to the lysosomal compartments of the cells and no significant difference (P = 0.196) between the two orientations of chimera (Fig. 1F). Together, these results confirm that the LTM is capable of binding HBEGF and trafficking associated cargo into cells and that the LTM can function in this manner at either terminus of a fusion construct.

With minimal positional bias observed in the mCherry fusion proteins, we next screened LTM fusions to TPP1 to identify a design that maximizes expression, stability, activity, and, ultimately, delivery. TPP1 is a 60-kDa lysosomal serine peptidase encoded by the CLN2 gene, implicated in neuronal ceroid lipofuscinosis type 2 or Batten disease. Loss of function results in the accumulation of lipofuscin, a proteinaceous, autofluorescent storage material (13). Exposure to the low-pH environment of the lysosome triggers autoproteolytic activation of TPP1 and release of a 20-kDa propeptide that occludes its active site. From a design perspective, we favored an orientation in which the LTM was N terminal to TPP1, as autoprocessing of TPP1 would result in the release of the upstream LTM-TPP1 propeptide, liberating active, mature TPP1 enzyme in the lysosome (Fig. 2A). Given the need for mammalian expression of lysosomal enzymes, we generated synthetic genetic fusions of the LTM to TPP1, in which we converted the codons from bacterially derived DT into the corresponding mammalian codons. Human embryonic kidney (HEK) 293F suspension cells stably expressing recombinant TPP1 (rTPP1) and TPP1 with an N-terminal LTM fusion (LTM-TPP1) were generated using the piggyBac transposon system (14). A C-terminal construct (TPP1-LTM) was also produced; however, expression of this chimera was poor in comparison with rTPP1 and LTM-TPP1 (~0.4 mg/liter, cf. 10 to 15 mg/liter).

(A) Design of LTM-TPP1 fusion protein and delivery schematic. (B) Enzyme kinetics of rTPP1 and LTM-TPP1 against the synthetic substrate AAF-AMC are indistinguishable. Michaelis-Menten plots were generated by varying [AAF-AMC] at a constant concentration of 10 nM enzyme (means SD; n = 3). Plots and kinetic parameters were calculated with GraphPad Prism 7.04. (C) Maturation of TPP1 is unaffected by the N-terminal fusion of LTM. (D) LTM-TPP1 inhibits wild-type DT activity in a dose-dependent manner (IC50 of 17.2 nM), while rTPP1 has no effect on protein synthesis inhibition by DT (means SD; n = 3). (E) LTM and DTR-TPP1 bind HBEGF with apparent Kds of 13.3 and 19.1 nM, respectively. (F) LTM-TPP1 (39) colocalizes with LAMP1 staining (red).

The activity of rTPP1 and LTM-TPP1 against the tripeptide substrate Ala-Ala-Phe-AMC (AAF-AMC) was assessed to determine any effects of the LTM on TPP1 activity. The enzyme activities of rTPP1 and LTM-TPP1 were determined to be equivalent, as evidenced through measurements of their catalytic efficiency (Fig. 2B), demonstrating that there is no inference by LTM on the peptidase activity of TPP1. Maturation of LTM-TPP1 through autocatalytic cleavage of the N-terminal propeptide was analyzed by SDSpolyacrylamide gel electrophoresis (PAGE) (Fig. 2C). Complete processing of the zymogen at pH 3.5 and 37C occurred between 5 and 10 min, which is consistent with what has been observed for the native recombinant enzyme (15).

The ability of LTM-TPP1 to compete with DT for binding to extracellular HBEGF was first assessed with the protein synthesis competition assay. Similar to LTM, mCherry-LTM, and LTM-mCherry, LTM-TPP1 prevents protein synthesis inhibition by 10 pM DT with an IC50 (median inhibitory concentration) of 17.2 nM (Fig. 2D). As expected, rTPP1 alone was unable to inhibit DT-mediated entry and cytotoxicity. To further characterize this interaction, we measured the interaction between LTM and LTM-TPP1 and recombinant HBEGF using surface plasmon resonance (SPR) binding analysis (Fig. 2E). By SPR, LTM and LTM-TPP1 were calculated to have apparent Kds of 13.3 and 19.1 nM, respectively, values closely corresponding to the IC50 values obtained from the competition experiments (10.1 and 17.2 nM, respectively). Consistent with these results, LTM-TPP1 colocalizes with LAMP1 by immunofluorescence (Fig. 2F).

To study uptake of chimeric fusion proteins in cell culture, we generated a cell line deficient in TPP1 activity. A CRISPR RNA (crRNA) was designed to target the signal peptide region of TPP1 in exon 2 of CLN2. Human HeLa Kyoto cells were reverse transfected with a Cas9 ribonucleoprotein complex and then seeded at low density into a 10-cm dish. Single cells were expanded to colonies, which were picked and screened for TPP1 activity. A single clone deficient in TPP1 activity was isolated and expanded, which was determined to have ~4% TPP1 activity relative to wild-type HeLa Kyoto cells plated at the same density (Fig. 3A). The small residual activity observed is likely the result of another cellular enzyme processing the AAFAMC (7-amido-4-methlycoumarin) substrate used in this assay, as there is no apparent TPP1 protein being produced (Fig. 3B). Sanger sequencing of the individual alleles confirmed complete disruption of the CLN2 gene (fig. S1). In total, three unique mutations were identified within exon 2 of CLN2: a single base insertion resulting in a frameshift mutation and two deletions of 24 and 33 base pairs (bp), respectively.

(A) CLN2 knockout cells exhibit ~4% TPP1 activity relative to wild-type HeLa Kyoto cells (means SD; n = 3). (B) Western blotting against TPP1 reveals no detectable protein in the knockout cells. (C) (Left) In vitro maturation of pro-rTPP1 and LTM-TPP1 (16 ng) was analyzed by Western blot. (Right) TPP1 present in wild-type (WT) and TPP1/ cells, and TPP1/ cells treated with 100 nM rTPP1 and LTM-TPP1. (D) Uptake of rTPP1 and LTM-TPP1 into HeLa Kyoto TPP1/ cells was monitored by TPP1 activity (means SD; n = 4). (E) TPP1 activity present in HeLa Kyoto TPP1/ cells following a single treatment with 50 nM LTM-TPP1 (means SD; n = 3).

Next, we compared the delivery and activation of rTPP1 and LTM-TPP1 into lysosomes by treating TPP1/ cells with a fixed concentration of the enzymes (100 nM) and by analyzing entry and processing by Western blot (Fig. 3C). In both cases, most enzymes were present in the mature form, indicating successful delivery to the lysosome; however, the uptake of LTM-TPP1 greatly exceeded the uptake of rTPP1. As both rTPP1 and LTM-TPP1 receive the same M6P posttranslational modifications promoting their uptake by CIMPR, differences in their respective uptake should be directly attributable to uptake by HBEGF. To quantify the difference in uptake and lysosomal delivery, cells were treated overnight with varying amounts of each enzyme, washed, lysed, and assayed for TPP1 activity. The activity assays were performed without a preactivation step, so signal represents protein that has been activated in the lysosome. For both constructs, we observed a dose-dependent increase in delivery of TPP1 to the lysosome (Fig. 3D). Delivery of LTM-TPP1 was significantly enhanced compared with TPP1 alone at all doses, further demonstrating that uptake by HBEGF is more efficient than that by CIMPR alone. TPP1 activity in cells treated with LTM-TPP1 was consistently ~10 greater than that of cells treated with rTPP1, with the relative difference increasing at the highest concentrations tested. This may speak to differences in abundance, replenishment, and/or recycling of HBEGF versus CIMPR, in addition to differences in receptor-ligand affinity. Uptake of LTM-TPP1 and rTPP1 into several other cell types yielded similar results (fig. S2). To assess the lifetime of the delivered enzyme, cells were treated with LTM-TPP1 (50 nM) and incubated overnight. Cells were washed and incubated with fresh media, and TPP1 activity was assayed over the course of several days. Cells treated with LTM-TPP1 still retained measurable TPP1 activity at 1 week after treatment (Fig. 3E).

While the DT competition experiment demonstrated that HBEGF is involved in the uptake of LTM-TPP1 but not rTPP1 (Fig. 2D), it does not account for the contribution of CIMPR to uptake. Endoglycosidase H (EndoH) cleaves between the core N-acetylglucosamine residues of high-mannose N-linked glycans, leaving behind only the asparagine-linked N-acetylglucosamine moiety. Both rTPP1 and LTM-TPP1 were treated with EndoH to remove any M6P moieties, and delivery into Hela TPP1/ was subsequently assessed. While rTPP1 uptake is completely abrogated by treatment with EndoH, LTM-TPP1 uptake is only partially decreased (Fig. 4), indicating that while HBEGF-mediated endocytosis is the principal means by which LTM-TPP1 is taken up into cells, uptake via CIMPR still occurs. The fact that CIMPR uptake is still possible in the LTM-TPP1 fusion means that the fusion is targeted to two receptors simultaneously, increasing its total uptake and, potentially, its biodistribution.

Uptake of LTM-TPP1 via the combination of HBEGF and CIMPR was shown to be 3 to 20 more efficient than CIMPR alone in cellulo (fig. S2). To interrogate this effect in vivo, TPP1-deficient mice (TPP1tm1pLob or TPP1/) were obtained as a gift from P. Lobel at Rutgers University. Targeted disruption of the CLN2 gene was achieved by insertion of a neo cassette into intron 11 in combination with a point mutation (R446H), rendering these mice TPP1 null by both Western blot and enzyme activity assay (16). Prior studies have demonstrated that direct administration of rTPP1 into the cerebrospinal fluid (CSF) via intracerebroventricular or intrathecal injection results in amelioration of disease phenotype (17) and even extension of life span in the disease mouse (18). To compare the uptake of LTM-TPP1 and rTPP1 in vivo, the enzymes were injected into the left ventricle of 6-week-old TPP1/ mice. Mice were euthanized 24 hours after injection, and brain homogenates of wild-type littermates, untreated, and treated mice were assayed for TPP1 activity (Fig. 5A). Assays were performed without preactivation, and therefore, the results report on enzyme that has been taken up into cells, trafficked to the lysosome, and processed to the mature form.

(A) Assay schematic. (B) TPP1 activity in brain homogenates of 6-week-old mice injected with two doses (5 and 25 g) of either rTPP1 or LTM-TPP1 (5 g, P = 0.01; 25 g, P = 0.002). (C) TPP1 activity in brain homogenates following a single 25-g dose of LTM-TPP1, 1, 7, and 14 days postinjection. Data are presented as box and whisker plots, with whiskers representing minimum and maximum values from n 4 mice per group. Statistical significance was calculated using paired t tests with GraphPad Prism 7.04.

While both enzymes resulted in a dose-dependent increase in TPP1 activity, low (5 g) and high (25 g) doses of rTPP1 resulted in only modest increases of activity, representing ~6 and ~26% of the wild-type levels of activity, respectively (Fig. 5B). At the same doses, LTM-TPP1 restored ~31 and ~103% of the wild-type activity. To assess the lifetime of enzyme in the brain, mice were injected intracerebroventricularly with 25 g of LTM-TPP1 and euthanized either 1 or 2 weeks postinjection. Remarkably, at 1 week postinjection, ~68% of TPP1 activity was retained (compared with 1 day postinjection), and after 2 weeks, activity was reduced to ~31% (Fig. 5C).

ERT is a lifesaving therapy that is a principal method of treatment in non-neurological LSDs. Uptake of M6P-labeled enzymes by CIMPR is relatively ineffective due to variable receptor affinity (5, 6), heterogeneous expression of the receptor, and incomplete labeling of recombinantly produced enzymes (19). Despite its inefficiencies and high cost (~200,000 USD per patient per year) (20), it remains the standard of care for several LSDs, as alternative treatment modalities (substrate reduction therapy, gene therapy, and hematopoietic stem cell transplantation) are not effective, not as well developed, or inherently riskier (2125). Improving the efficiency and distribution of recombinant enzyme uptake may help address some of the current shortcomings in traditional ERT.

Several strategies have been used to increase the extent of M6P labeling on recombinantly produced lysosomal enzymes: engineering mammalian and yeast cell lines to produce more specific/uniform N-glycan modification (19, 26, 27), chemical or enzymatic modification of N-glycans posttranslationally (28), and covalent coupling of M6P (29). M6P-independent uptake of a lysosomal hydrolase by CIMPR has been demonstrated for both -glucuronidase (28) and acid -glucosidase (30, 31). In the latter work, a peptide tag (GILT) targeting insulin-like growth factor II receptor (IGF2R) was fused to recombinant alpha glucosidase, which enabled receptor-mediated entry into cells. CIMPR is a ~300-kDa, 15-domain membrane protein with 3 M6P-binding domains and 1 IGF2R domain. By targeting the IGF2R domain with a high-affinity (low nanomolar) peptide rather than the low-affinity M6P-binding domain, the authors were able to demonstrate a >20-fold increase in the uptake of a GAA-peptide fusion protein in cell culture and a ~5-fold increase in the ability to clear built-up muscle glycogen in GAA-deficient mice.

In this study, we have demonstrated efficient uptake and lysosomal trafficking of a model lysosomal enzyme, TPP1, via a CIMPR-independent route, using the receptor-binding domain of a bacterial toxin. HBEGF is a member of the EGF family of growth factors, and DT is its only known ligand. Notably, it plays roles in cardiac development, wound healing, muscle contraction, and neurogenesis; however, it does not act as a receptor in any of these physiological processes (32). Intracellular intoxication by DT is the only known process in which HBEGF acts as a receptor, making it an excellent candidate receptor for ERT, as there is no natural ligand with which to compete. Upon binding, DT is internalized via clathrin-mediated endocytosis and then trafficked toward lysosomes for degradation (33, 34). Acidification of endosomal vesicles by vacuolar ATPases (adenosine triphosphatases) promotes insertion of DTT into the endosomal membrane and subsequent translocation of the catalytic DTC domain into the cytosol. In the absence of an escape mechanism, the majority of internalized LTM should be trafficked to the lysosome, as we have demonstrated with our chimera (Figs. 2F and 3C). Uptake of LTM-TPP1 in vitro is robustly relative to rTPP1 (Fig. 3D and fig. S2), and TPP1 activity is sustained in the lysosome for a substantial length of time (Fig. 3E). We have also demonstrated that the increase in uptake efficiency that we observed in cell culture persists in vivo. TPP1 activity in the brains of CLN2-null mice was significantly greater in animals treated with intracerebroventricularly injected LTM-TPP1, as compared with those treated with TPP1 at two different doses (Fig. 5B), and, remarkably, this activity persists with an apparent half-life of ~8 days (Fig. 5C).

An important consideration for further development of the LTM platform for clinical development is the potential immunogenicity of using a bacterial fragment in this context. Previously, we demonstrated that the receptor-binding fragment of DT could be replaced with a human scFv (single-chain fragment variable) targeting HBEGF (8). With our demonstration of the potential for targeting HBEGF for LSDs, future efforts will focus on increasing the affinity and specificity of these first-generation humanized LTMs to develop high-affinity chimeras with greatly reduced immunogenicity for further development.

While the ability of LTM-TPP1 to affect disease progression has yet to be determined, recent positive clinical trial results (35) and the subsequent approval of rTPP1 (cerliponase alfa) for treatment of neuronal ceroid lipofuscinosis 2 (NCL2) provide support for this approach. In that clinical trial, 300 mg of rTPP1 was administered by biweekly intracerebroventricular injection to 24 affected children, and this was able to prevent disease progression. While this dose is of the same order of magnitude as other approved ERTs (<1 to 40 mg/kg) (36, 37), it represents a substantial dose, especially considering that it was delivered to a single organ. Improving the efficiency of uptake by targeting an additional receptor as we have done here, is expected to greatly decrease the dose required to improve symptoms, while at the same time decreasing costs and the chances of dose-dependent side effects.

DTK51E/E148K, LTM, LTM-mCherry, mCherry-LTM, and HBEGF constructs were cloned using the In-Fusion HD cloning kit (Clontech) into the Champion pET SUMO expression system (Invitrogen). Recombinant proteins were expressed as 6His-SUMO fusion proteins in Escherichia coli BL21(DE3)pLysS cells. Cultures were grown at 37C until an OD600 (optical density at 600 nm) of 0.5, induced with 1 mM IPTG (isopropyl--d-thiogalactopyranoside) for 4 hours at 25C. Cell pellets harvested by centrifugation were resuspended in lysis buffer [20 mM tris (pH 8.0), 160 mM NaCl, 10 mM imidazole, lysozyme, benzonase, and protease inhibitor cocktail] and lysed by three passages through an EmulsiFlex C3 microfluidizer (Avestin). Following clarification by centrifugation at 18,000g for 20 min and syringe filtration (0.2 m), soluble lysate was loaded over a 5-ml His-trap FF column (GE Healthcare) using an AKTA FPLC. Bound protein was washed and eluted over an imidazole gradient (20 to 150 mM). Fractions were assessed for purity by SDS-PAGE, pooled, concentrated, and frozen on dry ice in 25% glycerol for storage at 80C.

TPP1 cDNA was obtained from the SPARC BioCentre (The Hospital for Sick Children) and cloned into the piggyBac plasmid pB-T-PAF (J.M.R., University of Toronto) using Not I and Asc I restriction sites to generate two expression constructs (pB-T-PAF-ProteinA-TEV-LTM-TPP1 and pB-T-PAF-ProteinA-TEV-TPP1). Stably transformed expression cell lines (HEK293F) were then generated using the piggyBac transposon system, as described (14). Protein expression was induced with doxycycline, and secreted fusion protein was separated from expression media using immunoglobulin G (IgG) Sepharose 6 fast flow resin (GE Healthcare) in a 10-ml Poly-Prep chromatography column (Bio-Rad). Resin was washed with 50 column volumes of wash buffer [10 mM tris (pH 7.5) and 150 mM NaCl] and then incubated overnight at 4C with TEV (Tobacco Etch Virus) protease to release the recombinant enzyme from the Protein A tag. Purified protein was then concentrated and frozen on dry ice in 50% glycerol for storage at 80C.

Cellular intoxication by DT was measured using a nanoluciferase reporter strain of Vero cells (Vero NlucP), as described previously (8). Briefly, Vero NlucP cells were treated with a fixed dose of DT at EC99 (10 pM) and a serial dilution of LTM, LTM-mCherry, mCherry-LTM, DTK51E/E148K, LTM-TPP1, or rTPP1 and incubated overnight (17 hours) at 37C. Cell media was then replaced with a 1:1 mixture of fresh media and Nano-Glo luciferase reagent (Promega), and luminescence was measured using a SpectraMax M5e (Molecular Devices). Results were analyzed with GraphPad Prism 7.04.

SPR analysis was performed on a Biacore X100 system (GE Healthcare) using a CM5 sensor chip. Recombinant HBEGF was immobilized to the chip using standard amine coupling at a concentration of 25 g/ml in 10 mM sodium acetate (pH 6.0) with a final response of 1000 to 2500 resonance units (RU). LTM and LTM-TPP1 were diluted in running buffer [200 mM NaCl, 0.02% Tween 20, and 20 mM tris (pH 7.5)] at concentrations of 6.25 to 100 nM and injected in the multicycle analysis mode with a contact time of 180 s and a dissociation time of 600 s. The chip was regenerated between cycles with 10 mM glycine (pH 1.8). Experiments were performed in duplicate using two different chips. Binding data were analyzed with Biacore X100 Evaluation Software version 2.0.2, with apparent dissociation constants calculated using the 1:1 steady-state affinity model.

HeLa cells were incubated with LTM-mCherry (0.5 M), mCherry-LTM (0.5 M), or LTM-TPP1 (2 M) for 2 hours. Cells were washed with ice-cold phosphate-buffered saline (PBS), fixed with 4% paraformaldehyde, and permeabilized with 0.5% Triton X-100. mCherry constructs were visualized with a rabbit polyclonal antibody against mCherry (Abcam, ab16745) and anti-rabbit Alexa Fluor 568 (Thermo Fisher Scientific). LAMP1 was stained with a mouse primary antibody (DSHB 1D4B) and anti-mouse Alexa Fluor 488 (Thermo Fisher Scientific).

Colocalization was quantified using the Volocity (PerkinElmer) software package to measure Manders coefficients of mCherry signal with LAMP1 signal. The minimal threshold for the 488- and 568-nm channels was adjusted to correct the background signal. The same threshold for both channels was used for all the cells examined.

CLN2/ fibroblast 19494 were incubated with LTM-TPP1 (2 M) for 2 hours. Cells were washed with ice-cold PBS, fixed with 4% paraformaldehyde, and permeabilized with 0.5% Triton X-100. LTM-TPP1 was visualized with a mouse monoclonal against TPP1 (Abcam, ab54685) and anti-mouse Alexa Fluor 488 (Thermo Fisher Scientific). LAMP1 was stained with rabbit anti-LAMP1 and anti-rabbit Alexa Fluor 568 (Thermo Fisher Scientific).

TPP1 protease activity was measured using the synthetic substrate AAF-AMC using a protocol adapted from Vines and Warburton (38). Briefly, enzyme was preactivated in 25 l of activation buffer [50 mM NaOAc (pH 3.5) and 100 mM NaCl] for 1 hour at 37C. Assay buffer [50 mM NaOAc (pH 5.0) and 100 mM NaCl] and substrate (200 M AAF-AMC) were then added to a final volume of 100 l. Fluorescence (380 nm excitation/460 nm emission) arising from the release of AMC was monitored in real time using a SpectraMax M5e (Molecular Devices). TPP1 activity in cellulo was measured similarly, without the activation step. Cells in a 96-well plate were incubated with 25 l of 0.5% Triton X-100 in PBS, which was then transferred to a black 96-well plate containing 75 l of assay buffer with substrate in each well.

crRNA targeting the signal peptide sequence in exon 2 of CLN2 was designed using the Integrated DNA Technologies (www.idtdna.com) design tool. The gRNA:Cas9 ribonucleoprotein complex was assembled according to the manufacturers protocol (Integrated DNA Technologies) and reverse transfected using Lipofectamine RNAiMAX (Thermo Fisher Scientific) into HeLa Kyoto cells (40,000 cells in a 96-well plate). Following 48 hours of incubation, 5000 cells were seeded into a 10-cm dish. Clonal colonies were picked after 14 days and transferred to a 96-well plate. Clones were screened for successful CLN2 knockout by assaying TPP1 activity and confirmed by Sanger sequencing and Western blot against TPP1 antibody (Abcam, ab54385).

The pro-form of TPP1 was matured in vitro to the active form in 50 mM NaOAc (pH 3.5) and 100 mM NaCl for 1 to 30 min at 37C. The autoactivation reaction was halted by the addition of 2 Laemmli SDS sample buffer containing 10% 2-mercaptoethanol and boiled for 5 min. Pro and mature TPP1 were separated by SDS-PAGE and imaged on a ChemiDoc gel imaging system (Bio-Rad).

Proteins or cellular lysate were separated by 4 to 20% gradient SDS-PAGE before being transferred to a nitrocellulose membrane using the iBlot (Invitrogen) dry transfer system. Membranes were then blocked for 1 hour with a 5% milktris-buffered saline (TBS) solution and incubated overnight at room temperature with a 1:100 dilution of mouse monoclonal antibody against TPP1 (Abcam, ab54685) in 5% milk-TBS. Membranes were washed 3 5 min with 0.1% Tween 20 (Sigma-Aldrich) in TBS before a 1-hour incubation with a 1:5000 dilution of sheep anti-mouse IgG horseradish peroxidase secondary antibody (GE Healthcare) in 5% milk-TBS. Chemiluminescent signal was developed with Clarity Western ECL substrate (Bio-Rad) and visualized on a ChemiDoc gel imaging system (Bio-Rad).

rTTP1 and LTM-TPP1 were treated with EndoH (New England Biolabs) to remove N-glycan modifications. Enzymes were incubated at 1 mg/ml with 2500 U of EndoH for 48 hours at room temperature in 20 mM tris (pH 8.0) and 150 mM NaCl in a total reaction volume of 20 l. Cleavage of N-glycans was assessed by SDS-PAGE, and concentrations were normalized to native enzyme-specific activities.

Cryopreserved TPP1+/ embryos were obtained from P. Lobel at Rutgers University and rederived in a C57/BL6 background at The Centre for Phenogenomics in Toronto. Animal maintenance and all procedures were approved by The Centre for Phenogenomics Animal Care Committee and are in compliance with the CCAC (Canadian Council on Animal Care) guidelines and the OMAFRA (Ontario Ministry of Agriculture, Food, and Rural Affairs) Animals for Research Act.

TPP1/ mice (60 days old) were anesthetized with isoflurane (inhaled) and injected subcutaneously with sterile saline (1 ml) and meloxicam (2 mg/kg). Mice were secured to a stereotactic system, a small area of the head was shaved, and a single incision was made to expose the skull. A high-speed burr was used to drill a hole at stereotaxic coordinates: anteroposterior (A/P), 1.0 mm; mediolateral (M/L), 0.3 mm; and dorsoventral (D/V), 3.0 mm relative to the bregma, and a 33-gauge needle attached to a 10-l Hamilton syringe was used to perform the intracerebroventricular injection into the left ventricle. Animals received either 1 or 5 l of enzyme (5 g/l), injected at a constant rate. Isoflurane-anesthetized animals were euthanized by transcardial perfusion with PBS. Brains were harvested and frozen immediately, then thawed and homogenized in lysis buffer [500 mM NaCl, 0.5% Triton X-100, 0.1% SDS, and 50 mM Tris (pH 8.0)] using 5-mm stainless steel beads in TissueLyser II (Qiagen). In vitro TPP1 assay was performed, as described, minus the activation step.

Acknowledgments: We thank P. Lobel at Rutgers University for providing the TPP1-deficient mice. Funding: We are grateful to the Canadian Institutes of Health Research for funding. Author contributions: S.N.S.-M. devised and performed experiments and drafted the initial manuscript. G.L.B. provided materials and assisted in conceptualization and experimental design. X.Z., D.Z., and R.H. contributed to the experimental design and performed experiments. P.K.K. and B.A.M. contributed to the experimental design. J.M.R. contributed to the experimental design and revised the manuscript. R.A.M. assisted in conceptualization, contributed to the experimental design, and assisted in writing the manuscript. Competing interests: B.A.M. is a chief medical advisor at Taysha Gene Therapies. The authors declare that they have no other competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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Exploiting the diphtheria toxin internalization receptor enhances delivery of proteins to lysosomes for enzyme replacement therapy - Science Advances

Cardiac Stem Cells Comments Off on Exploiting the diphtheria toxin internalization receptor enhances delivery of proteins to lysosomes for enzyme replacement therapy – Science Advances | December 13th, 2020

REDWOOD CITY, Calif.--(BUSINESS WIRE)--Jasper Therapeutics, Inc., a biotechnology company focused on hematopoietic cell transplant therapies, today announced clinical data from its ongoing multicenter Phase 1 clinical trial of JSP191, a first-in-class anti-CD117 monoclonal antibody, in patients with severe combined immune deficiency (SCID). The trial is evaluating JSP191 as a conditioning agent to enable stem cell transplantation in patients with SCID who are either transplant-naive or who received a prior stem cell transplant with a poor outcome.

Data from the first transplant-nave SCID patient in the Phase 1 trial, a 6-month-old infant, showed that a single dose of JSP191 administered prior to stem cell transplant was effective in establishing sustained donor chimerism followed by development of B, T and NK immune cells. No treatment-related adverse events were reported. The data were presented by primary investigator Rajni Agrawal-Hashmi, M.D., of Stanford University, at the 62nd American Society of Hematology (ASH) Annual Meeting & Exposition.

We have previously shown that JSP191 can be successfully used as a single conditioning agent in SCID patients who had failed a previous transplant, said Kevin N. Heller, M.D., Executive Vice President, Research and Development, of Jasper Therapeutics. This new data presented at ASH 2020 showing success in an infant with SCID undergoing a first transplant provides proof of concept of the safety and efficacy of the use of JSP191 as an alternative to genotoxic chemotherapies currently used to deplete stem cells prior to transplant.

Hematopoietic cell transplantation offers the only curative therapy for SCID, a severe genetic immune disorder that leaves patients without a functioning immune system. With this approach, standard-of-care chemotherapeutic conditioning regimens are given prior to transplant to reduce the number of blood stem cells in the bone marrow to make space for donor blood stem cells to engraft and cure the patient. JSP191 is designed to replace the need for chemotherapeutic conditioning agents, which are DNA-damaging and highly toxic.

Dr. Heller added, With our Phase 1 trials in SCID and hematologic disorders underway, we are planning to expand the development of JSP191 into additional indications, such as gene therapies, autoimmune diseases, Fanconis anemia and other rare disorders that can be cured by stem cell transplant.

The open-label, multicenter Phase 1 study is evaluating the safety, tolerability and efficacy of JSP191 as a conditioning agent in patients with SCID undergoing first or repeat hematopoietic cell transplantation. Up to three different doses of JSP191 are being assessed for dose-limiting toxicities. The trial is currently open for enrollment at Stanford University, the University of California, San Francisco, Memorial Sloan Kettering Cancer Center, the University of California, Los Angeles, and Cincinnati Childrens Hospital. Additional clinical trial sites in the United States will initiate enrollment in the coming weeks.

About SCID

Severe combined immune deficiency (SCID) is a group of rare disorders caused by mutations in genes involved in the development and function of infection-fighting immune cells. Infants with SCID appear healthy at birth but are highly susceptible to severe infections. The condition is fatal, usually within the first year or two of life, unless infants receive immune-restoring treatments, such as transplants of blood-forming stem cells, gene therapy or enzyme therapy.

About JSP191

JSP191 (formerly AMG 191) is a first-in-class humanized monoclonal antibody in clinical development as a conditioning agent that clears hematopoietic stem cells from bone marrow. JSP191 binds to human CD117, a receptor for stem cell factor (SCF) that is expressed on the surface of hematopoietic stem and progenitor cells. The interaction of SCF and CD117 is required for stem cells to survive. JSP191 blocks SCF from binding to CD117 and disrupts critical survival signals, causing the stem cells to undergo cell death and creating an empty space in the bone marrow for donor or gene-corrected transplanted stem cells to engraft.

Preclinical studies have shown that JSP191 as a single agent safely depletes normal and diseased hematopoietic stem cells, including in animal models of SCID, myelodysplastic syndromes (MDS) and sickle cell disease (SCD). Treatment with JSP191 creates the space needed for transplanted normal donor or gene-corrected hematopoietic stem cells to successfully engraft in the host bone marrow. To date, JSP191 has been evaluated in more than 90 healthy volunteers and patients.

JSP191 is currently being evaluated as a sole conditioning agent in a Phase 1/2 dose-escalation and expansion trial to achieve donor stem cell engraftment in patients undergoing hematopoietic cell transplant for severe combined immunodeficiency (SCID), which is potentially curable only by this type of treatment. JSP191 is also being evaluated in a Phase 1 study in patients with MDS or acute myeloid leukemia (AML) who are receiving hematopoietic cell transplant. For more information about the design of these clinical trials, visit http://www.clinicaltrials.gov (NCT02963064 and NCT04429191). Additional studies are planned to advance JSP191 as a conditioning agent for patients with other rare and ultra-rare monogenic disorders and autoimmune diseases.

About Jasper Therapeutics

Jasper Therapeutics is a biotechnology company focused on the development of novel curative therapies based on the biology of the hematopoietic stem cell. The companys lead compound, JSP191, is in clinical development as a conditioning antibody that clears hematopoietic stem cells from bone marrow in patients undergoing a hematopoietic cell transplant. This first-in-class conditioning antibody is designed to enable safer and more effective curative hematopoietic cell transplants and gene therapies. For more information, please visit us at jaspertherapeutics.com.

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Jasper Therapeutics Announces Data from First Transplant-naive Patient in Phase 1 Clinical Trial of JSP191 as Conditioning Agent in Patients with SCID...

Bone Marrow Stem Cells Comments Off on Jasper Therapeutics Announces Data from First Transplant-naive Patient in Phase 1 Clinical Trial of JSP191 as Conditioning Agent in Patients with SCID… | December 13th, 2020

DUARTE, Calif.--(BUSINESS WIRE)--City of Hope doctors participated in research presented at the American Society of Hematology (ASH) virtual meeting, Dec. 5 to 8, that are helping advance the treatment of blood cancers, including one study which demonstrated allogeneic stem cell transplants do have a survival benefit for older adults with myelodysplastic syndromes (MDS) compared with current standard of care.

The study is the largest and most definitive trial to demonstrate the benefits of an allogeneic stem cell transplantation for older adults with MDS, and is just one of numerous studies that City of Hope doctors help lead with the aim of finding more effective treatments of various blood cancers.

This years ASH conference truly showcases City of Hopes leadership in finding more effective treatments for blood cancers, said Stephen J. Forman, M.D., director of City of Hopes Hematologic Malignancies Research Institute. Whether its finding innovative treatments to make it possible for more older adults with cancer to receive stem cell transplants, or pursuing therapies that are more effective with fewer side effects, City of Hope doctors continue to lead innovative research in blood cancers and other hematological malignancies.

City of Hope doctors are leading novel clinical trials for patients with leukemia, lymphoma and other blood cancers.

Multicenter clinical trial led by City of Hope makes stem cell transplant possible for older adults with myelodysplastic syndromes

Allogeneic hematopoietic cell transplantation, or stem cell/bone marrow transplants, for blood cancers that have recurred or are difficult to treat can put the disease into long-term remission and provide a potential cure. The therapy establishes a new, disease-free blood and immune system by transplanting healthy blood stem cells from a donor into a cancer patient after destroying the patients unhealthy bone marrow.

City of Hope and other institutions started this therapy in 1976, primarily for younger patients with blood cancers. The therapy involves using high-dose chemotherapy and/or radiotherapy to make room for a person to receive new stem cells; serious side effects can also occur after transplant. Because of these and other considerations, for many years, older adults with blood cancers have not been considered for transplants.

City of Hope has been leading the way to make transplants possible for more older adults with various cancers.

A new study presented at ASH demonstrates transplants are now a possibility and beneficial for patients with myelodysplastic syndromes (MDS). Approximately 13,000 people in the United States each year are diagnosed with MDS, an umbrella term describing several blood disorders that begin in the bone marrow.

Co-led by City of Hopes Ryotaro Nakamura, M.D., director of City of Hopes Center for Stem Cell Transplantation, the study is the largest and first trial to demonstrate the benefits of an allogeneic stem cell transplantation for older adults with MDS as opposed to the standard of care currently provided to these patients. The multicenter trial for patients aged 50 to 75 with serious MDS compared how long transplant patients survived with those who didnt receive a transplant, as well as disease progression and quality of life. The transplant therapy used reduced-intensity conditioning, which delivers less chemotherapy and radiation before transplant and relies more on the anti-tumor effects of the therapy.

Between 2014 and 2018, the study enrolled 384 participants at 34 cancer centers nationwide. It included 260 patients who were able to find a donor for a transplant, as well as 124 patients who did not find a donor for a transplant.

After three years, nearly 48% of MDS patients who found a donor for transplant had survived compared with about 27% of those patients who didnt have a donor for transplant and received current hypomethylating therapy, a type of chemotherapy that is current standard of care for MDS. Leukemia-free survival which is relevant because myelodysplastic syndrome can develop into leukemia was also greater in transplant recipients after three years nearly 36% compared with about 21% for those who did not have a transplant.

There was a large and significant improvement in survival for patients who had a transplant, Nakamura said. The benefit margin in overall survival was over 20% (21.3%) for patients who had a transplant.

In addition, quality of life was the same for both transplant and nontransplant patients. There were no clinically significant differences when taking such measurements as physical and mental competency scores.

This is an extremely exciting study because it provides evidence that stem cell transplant is highly beneficial for older patients with serious MDS and will likely be practice-changing for this group, Nakamura said. Before, many doctors wouldnt even consider a transplant for this group of patients, but our study demonstrates that these patients should be evaluated for a transplant, which could potentially provide a cure for their disease.

The trial is part of Blood and Marrow Transplant Clinical Trials Network, which was established with support from the National Heart, Lung, and Blood Institute and National Cancer Institute, because of a critical need for multi-institutional clinical trials focused directly on improving survival for patients undergoing hematopoietic cell transplantation.

Updated results from a study of a potential new CAR T cell therapy, liso-cel, for relapsed/refractory chronic lymphocytic leukemia

Patients with relapsed or difficult-to-treat chronic lymphocytic leukemia/small lymphocytic leukemia continue to do well 24 months after receiving lisocabtagene maraleucel (liso-cel) chimeric antigen receptor (CAR) T cells, according to Tanya Siddiqi, M.D., director of City of Hopes Chronic Lymphocytic Leukemia (CLL) Program, which is part of the Toni Stephenson Lymphoma Center. She presented these findings during the 2020 ASH annual meeting virtual conference.

Overall, 23 and 22 patients were evaluated for safety and efficacy in this phase 1 trial, respectively. Their median age was 66 and they had received a median of four prior therapies; all patients had received prior ibrutinib, which is one of the standard of care drugs for CLL.

The overall response rate, or patients whose CLL diminished after liso-cel CAR T cell therapy, was 82%, and 45% of patients also had complete responses, or remissions.

After 15 months of treatment, 53% of patients maintained their responses to the therapy, and six patients continued to be in remission. After 18 months, 50% of patients maintained their response, and there were five remissions. All seven patients who completed the 24-month study maintained their response. Median progression-free survival, or the amount of time the cancer did not worsen during and after treatment, was 18 months.

As early as 30 days after receiving liso-cel, about 75% of 20 patients evaluated for the therapys efficacy had undetectable minimal residual disease (MRD, or no detectable traces of cancer) in the blood and 65% had undetectable MRD in the marrow.

These are remarkable results for a group of patients that prior to this CAR T treatment had no good treatment options if they had already progressed on novel targeted therapies like ibrutinib and venetoclax, Siddiqi said. Liso-cel is providing new hope for CLL patients, and the remissions are also long lasting with few serious side effects.

Because of its safety and effectiveness in clinical trials, liso-cel, which targets the CD19 protein on cancer cells, may soon receive approval from the Food and Drug Administration as a commercial therapy for relapsed or refractory B cell lymphoma. City of Hope is also taking part in the phase 2 trial of liso-cel in CLL patients.

Consolidation treatment with brentuximab vedotin/nivolumab after auto stem cell transplant for relapsed/refractory Hodgkin lymphoma patients leads to 18-month progression free-survival

Patients who have Hodgkin lymphoma that has not been cured by initial treatment will usually receive more chemotherapy and an autologous hematopoietic cell transplant. But even after a stem cell transplant, recurrence of the lymphoma is possible.

This multicenter phase 2 clinical trial, led by City of Hope, examined whether treating patients with brentuximab vedotin (BV), an antibody-based treatment that targets delivery of chemotherapy only to Hodgkin lymphoma cells, and nivolumab, which works by blocking the PD-1 immune checkpoint pathway that Hodgkin lymphoma hijacks to evade the immune system, was safe and effective as consolidation to prevent disease recurrence after transplant in patients with high-risk Hodgkin lymphoma.

Alex Herrera, M.D., assistant professor in City of Hope's Department of Hematology & Hematopoietic Cell Transplantation, discussed 19-month progression-free survival for trial participants, as well as overall survival, safety and response rates during ASH.

Fifty-nine patients were enrolled in the trial. Patients received the consolidation treatment starting a median of 54 days after transplant, and received a median of eight cycles of the therapy. The 19-month progression-free survival in patients was 92%, and overall survival in patients was 98%. Only three patients relapsed after receiving BV and nivolumab consolidation after transplant, and one patient passed away due to PCP pneumonia unrelated to the study treatment.

The most common sides effects related to the treatment were peripheral neuropathy (51%), neutropenia (42%), fatigue (37%) and diarrhea (29%).

Using brentuximab vedotin and nivolumab after transplant is a promising approach for preventing relapse of Hodgkin lymphoma after transplant that merits further study, Herrera said.

City of Hope doctors published research on innovative approaches against graft-versus-host-disease

Historically, a bone marrow/stem cell transplant is more likely to be effective if patients have a donor who is a 100% match, or as close to that as possible. Finding that perfect match is more difficult for African Americans, Latinos, Asian Americans and other ethnic groups as bone marrow donor registries are still trying to increase the number of non-white donors.

Transplant doctors are also looking for ways to make the transplant more effective if a perfect match cant be found; donors who are not a 100% or close match are referred to as mismatched unrelated. One major barrier to these transplants being effective is a condition known as graft-versus-host-disease (GVHD). The condition, which is more common in transplants involving mismatched donors, is caused by donated cells that recognize the recipient's cells as foreign and attack them, damaging the skin, eyes, lungs, liver and digestive tract.

In order to help prevent GVHD, therapies can be given to patients after transplant. A prospective clinical trial at City of Hope examined whether using cyclophosphamide after an infusion of stem cells could prevent GVHD.

Thirty-eight patients were enrolled in the trial, which is the first to examine the use of cyclophosphamide in transplants with a mismatched unrelated donor.

With a median follow-up period of 18 months, 87% of patients had survived, and the majority did not relapse or develop severe GVHD.

During the first 100 days post-transplant, acute GVHD incidence was around 50%; most cases were mild to moderate while severe GVHD was only 15%. A year after transplant, 52% of patients had some form of chronic GVHD, but only 3% had moderate or severe chronic GVHD.

The trial also examined toxicities, infections and immune system recovery after the transplant.

Our study showed that patients who received a transplant from a mismatched unrelated donor using post-transplant cyclophosphamide had a comparable outcome to what we see in matched donor transplants with few cases of serious GVHD cases, said Monzr Al Malki, M.D., associate clinical professor of City of Hopes Department of Hematology & Hematopoietic Cell Transplantation and director of unrelated donor BMT and haploidentical transplant programs. Our data support further development of this therapy in transplant patients who would otherwise have no suitable donors and limited treatment options.

City of Hopes Anthony Stein, M.D., also led a pilot trial that examined whether a new treatment approach may reduce the rate of GVHD in patients with acute myelogenous leukemia (AML) who have received an allogeneic hematopoietic cell transplant. Although a transplant can put AML into remission, GVHD remains the main serious complication after transplant, impacting a patients quality of life and increasing health care costs.

Eighteen patients between the ages of 18 and 60 enrolled in the trial. Each patient received a novel conditioning regimen of total marrow and lymphoid irradiation, which targets a patients marrow and lymph nodes while reducing radiation to other parts of the body, and cyclophosphamide, a therapy that suppresses the immune system. Tacrolimus was also provided to patients.

Radiation was delivered twice daily on the fourth day before transplant and on the day of transplant without chemotherapy. Cyclophosphamide was given to patients on the third and fourth day after transplant.

There were mild to moderate toxicities. Acute GVHD developed in two patients and only one patient developed the most serious GVHD. Five patients developed mild chronic GVHD. Nearly 60% of patients had not developed GVHD or the condition had not worsened after a year.

After a year, all patients had survived, and 83% had not relapsed. After two years, nearly 86% of patients had survived, and the relapse number remained the same.

The therapeutic approach did not interfere with the transplant process as all patients engrafted, or the donors cells started to produce bone marrow and immune cells.

This is welcome news for AML patients who receive an allogeneic transplant and are concerned about developing GVHD, said Stein, associate director of City of Hope's Gehr Family Center for Leukemia Research. Our study demonstrated that using this new combination of therapies is safe and feasible and does not interfere with the engraftment process.

In addition, after a year, patients in this trial were no longer taking immunosuppressive therapy and had an improved quality of life, Stein said. He added that because many of the patients didnt have GVHD, health care costs after a year were also lower than if patients required treatment for the condition.

City of Hope now plans to start a larger phase 2 trial using this treatment approach.

Bispecific antibodies continue to show promise against blood cancers

Mosunetuzumab is a promising new immunotherapy for the treatment of relapsed/refractory non-Hodgkin lymphoma (NHL) that recently received breakthrough therapy designation from the Food and Drug Administration. The designation is intended to expedite the development and review of drugs for serious or life-threatening diseases.

Elizabeth Budde, M.D., Ph.D., assistant professor in City of Hope's Department of Hematology & Hematopoietic Cell Transplantation, is leading clinical trials that are showing how well mosunetuzumab works against NHL. At this years ASH, one trial discussed is how the therapy is working for patients with follicular lymphoma.

Mosunetuzumab is a bispecific antibody targeting both CD3 (a protein found on the surface on T cells) and CD20 on the surface of B cells. The therapy redirects T cells to engage and eliminate malignant B cells.

Sixty-two patients, ranging in age from 27 to 85 years old, were enrolled in the trial for follicular lymphoma. They received intravenous doses of mosunetuzumab.

Sixty-eight percent of the patients responded to the therapy, and 50% had a complete response, or went into remission. Consistent complete response rates occurred even in patients with double refractory disease and patients who received prior CAR T cell therapy. Median duration of response was approximately 20 months, and media progression free survival was nearly one year.

Side effects were reported in 60 patients with serious adverse effects in 22 patients. The most frequently reported serious side effects were hypophosphatemia, an electrolyte disorder, and neutropenia, a condition caused by low numbers of white blood cells. Fourteen patients experienced cytokine release syndrome, but none required extensive treatment for it.

Neurological side effects included headache, insomnia and dizziness.

Patients in this trial had high response rates and their disease remained in control for a year, Budde said. This is remarkable because many patients were no longer responding to other therapies.

About City of Hope

City of Hope is an independent biomedical research and treatment center for cancer, diabetes and other life-threatening diseases. Founded in 1913, City of Hope is a leader in bone marrow transplantation and immunotherapy such as CAR T cell therapy. City of Hopes translational research and personalized treatment protocols advance care throughout the world. Human synthetic insulin and numerous breakthrough cancer drugs are based on technology developed at the institution. A National Cancer Institute-designated comprehensive cancer center and a founding member of the National Comprehensive Cancer Network, City of Hope has been ranked among the nations Best Hospitals in cancer by U.S. News & World Report for 14 consecutive years. Its main campus is located near Los Angeles, with additional locations throughout Southern California. For more information about City of Hope, follow us on Facebook, Twitter, YouTube or Instagram.

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City of Hope Doctors Present Innovative Therapies to Better Treat Blood Cancers at American Society of Hematology Virtual Conference - Business Wire

Bone Marrow Stem Cells Comments Off on City of Hope Doctors Present Innovative Therapies to Better Treat Blood Cancers at American Society of Hematology Virtual Conference – Business Wire | December 13th, 2020

A FORMER hairdresser from Bournemouth is appealing for people to help raise money to have life-saving surgery in Mexico to get rid of her Multiple Sclerosis once and for all.

Having been admitted to Royal Bournemouth Hospital for a suspected stroke or brain tumour in March 2017, at the age of 47, Kirsten Hannibal was found to have multiple lesions on her brain and was diagnosed with CIS which later progressed to MS.

During lockdown, Kirsten has researched into different ways to stop Multiple Sclerosis dead in its tracks, one of them being Hematopoietic Stem Cell Transplantation.

Although the procedure, which involves the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, is not widely accessible in the UK, it is available in Mexico, considered a world class hub for HSCT.

However she must raise over 40,000 to cover flights to Mexico as well as the cost of the procedure.

Vicky Dixon has set up a crowdfunding page to raise money for Kirstens medical procedure.

In a statement written on her crowdfunding page, she said: Our family are joining forces to raise the money needed to send our Kirsten to Mexico for Hematopoietic Stem Cell Transplantation treatment that is not universally available on the NHS, but will hopefully give Kirsten a chance of a future; a life free of pain, disability and heart breaking challenges.

We hope that Kirsten can follow the footsteps of other British MS sufferers and go to Mexico, a world class centre for HSCT, and cheaper than the UK, at the cost of 43,500.

The first large, randomised control trial, and several meta-analyses of HSCT, have confirmed that HSCT is a very effective therapy. This is now tipping the scales for HSCT becoming a mainstream treatment for MS in Britain.

However, the treatment has to take place before the MS becomes too advanced, and as it will be years before HSCT might be offered more widely, Kirsten would by then be swallowed up by the MS and not a suitable candidate for treatment.

Kirsten is on the brink of becoming too disabled for this treatment, hence the urgency of our appeal.

Sadly, the 46-year-old is now travelling a path similar to one her family have walked before.

In 1984 her mother at the age of 32 was diagnosed with lymphoblastic leukaemia and the Echo covered the story.

Her mother underwent aggressive chemotherapy and was the receiver of a ground-breaking treatment with a bone marrow transplant.

She was the first patient to receive this treatment in the south and, whilst the treatment was deemed a success, sadly her mother died.

Lynda Smiths legacy lives on because her bravery in allowing this treatment to take place is now the lifeline to many children and adults alike who survive leukaemia.

The treatment Kirsten is looking to have is similar to her mothers treatment, except it would be her own bone marrow that would be harvested. She will then be given chemotherapy and then the day Kirsten longs for, freedom from the disease.

The new birthday she dreams of is a stem cell birthday celebrated when the bone marrow is put back into her body giving her the chance of stopping Multiple Sclerosis.

So far, Kirstens fundraising appeal has raised 4,535, just over 10 per cent of her target.

To donate, visit https://www.gofundme.com/f/multiple-sclerosis-and-an-urgent-bid-for-freedom?utm_source=customer&utm_medium=email&utm_campaign=p_cp+sharesheet.

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Bid to fund stem cell treatment in Mexico for woman with MS - Bournemouth Echo

Bone Marrow Stem Cells Comments Off on Bid to fund stem cell treatment in Mexico for woman with MS – Bournemouth Echo | December 13th, 2020

Our goal with omidubicel is to revolutionize the field of bone marrow transplantation and bring a potentially curative cell therapy option to thousands of patients who are in need of a bone marrow transplant, but lack a suitable stem cell donor. These results bring us one step closer towards that goal, said Julian Adams, Ph.D., chief executive officer of Gamida Cell. Whats more, transplantation with omidubicel has been shown to result in more rapid neutrophil engraftment, a decrease in the amount of time patients spend in hospital, and a reduction in infections. These are very meaningful outcomes for patients and may also lessen the financial costs of certain aspects of the transplant.

Gamida Cell previously reported top-line data for omidubicel. In October, the company reported that the omidubicel phase 3 study achieved its secondary endpoints, analyzed in all randomized patients (intent-to-treat). In May, Gamida Cell reported that the study achieved its primary endpoint, demonstrating a highly statistically significant reduction in time to neutrophil engraftment, a key milestone in a patients recovery from a bone marrow transplant.

These pivotal data form the basis of a Biologics License Application (BLA) that Gamida Cell expects to initiate on a rolling basis before the end of this year. Gamida Cell is preparing to be launch ready in anticipation of potential FDA approval as early as the fourth quarter of 2021, subject to ongoing FDA discussions on manufacturing, quality and other matters.

The live event will be available here. More information about the Phase 3 study of omidubicel and the other updates included in this release can be found in the Pipeline Deep Dive presentation on the Gamida Cell website immediately following the event.

Details of Phase 3 Endpoints

As previously reported, Gamida Cell achieved positive topline results from its Phase 3 clinical study evaluating the safety and efficacy of omidubicel. The median time to neutrophil engraftment was 12 days for patients randomized to omidubicel compared to 22 days for the comparator group (p<0.001). Neutrophil engraftment is a measure of how quickly the stem cells a patient receives in a transplant are established and begin to make healthy new cells, and rapid neutrophil engraftment has been associated with fewer infections and shorter hospitalizations.

Today, Gamida Cell announced the details of achieving all three of the prespecified secondary endpoints of the study, analyzed in all randomized patients (intent-to-treat). These secondary endpoints were the proportion of patients who achieved platelet engraftment by day 42, the proportion of patients with grade 2 or grade 3 bacterial or invasive fungal infections in the first 100 days following transplant, and the number of days alive and out of the hospital in the first 100 days following transplant. All three secondary endpoints demonstrated statistical significance in an intent-to-treat analysis.

Additionally, Gamida Cell reported that the exploratory endpoints in the study demonstrated a reduction in the cumulative incidence of viral infections.

The international, multi-center, randomized Phase 3 study for omidubicel was designed to evaluate the safety and efficacy of omidubicel in patients with hematologic malignancies undergoing allogeneic bone marrow transplant compared to a comparator group of patients who received a standard umbilical cord blood transplant.

The company anticipates reporting the full data set in a peer-reviewed setting in the first half of 2021.

Commercial Readiness

The company discussed the market potential for omidubicel and launch plans. These included quantifying the market opportunity and keys aspects for a successful launch.

As it prepares for the potential commercial launch of omidubicel, the company also announced plans for the Gamida Cell Assist program, which has been designed to focus on patient access and support of every individual and their caregiver at each step of the transplant process. Once the program is launched, the Gamida Cell Assist case management team would provide a consistent, single point of contact for patients and health care professionals. This team would work with the transplant center to track each individual patients omidubicel therapy and provide real-time updates on the status of the therapy. Gamida Cell Assist is also designed to provide additional services, including coverage and reimbursement support, and patient and caregiver support, which may include financial, travel, and lodging assistance.

At Gamida Cell we are inspired to cure, with the goal of pioneering new standards of care for patients with blood cancers and serious blood diseases, said Michele Korfin, chief operating and chief commercial officer of Gamida Cell. The transplant process can be challenging and complex for the patient, caregivers and the entire transplant care team. As we prepare for commercialization, we have developed Gamida Cell Assist to serve as a comprehensive support program to focus on assuring a positive patient experience with omidubicel. We are committed to supporting patients and their caregivers during every step of their journey and enabling what matters most, a successful clinical outcome that makes a meaningful difference for patients.

Update on Natural Killer Cell Therapy GDA-201

In an oral presentation at the recent American Society of Hematology (ASH) 62nd Annual Meeting, it was shown that GDA-201 was well tolerated and no dose limiting toxicities were observed in the Phase 1 clinical study. GDA-201 demonstrated significant clinical activity in patients with non-Hodgkin lymphoma, with 13 complete responses and one partial response observed in 19 patients, for a response rate of 74 percent. Full details of the presentation can be found in the press release.

Phase 2 Study of Omidubicel in Patients with Severe Aplastic Anemia

In a poster presentation at ASH, it was shown that patients with severe aplastic anemia treated with omidubicel achieved sustained early engraftment. These data, which were presented on December 5 by Mohamed Samour, M.D., Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, are the first evidence that omidubicel can result in rapid engraftment and can achieve sustained hematopoiesis in patients who are at high risk for graft failure with conventional umbilical cord blood transplant.

About Omidubicel

Omidubicel is an advanced cell therapy under development as a potential life-saving allogeneic hematopoietic stem cell (bone marrow) transplant solution for patients with hematologic malignancies (blood cancers). In both Phase 1/2 and Phase 3 clinical studies (NCT01816230, NCT02730299), omidubicel demonstrated rapid and durable time to engraftment and was generally well tolerated.12 Omidubicel is also being evaluated in a Phase 1/2 clinical study in patients with severe aplastic anemia (NCT03173937). The aplastic anemia investigational new drug application is currently filed with the FDA under the brand name CordIn, which is the same investigational development candidate as omidubicel. For more information on clinical trials of omidubicel, please visit http://www.clinicaltrials.gov.

Omidubicel is an investigational therapy, and its safety and efficacy have not been established by the U.S. Food and Drug Administration or any other health authority.

About GDA-201

Gamida Cell applied the capabilities of its NAM-based cell expansion technology to develop GDA-201, an innate natural killer (NK) cell immunotherapy for the treatment of hematologic and solid tumors in combination with standard of care antibody therapies. GDA-201 addresses key limitations of NK cells by increasing the cytotoxicity and in vivo retention and proliferation in the bone marrow and lymphoid organs of NK cells expanded in culture. GDA-201 is in Phase 1 development through an investigator-sponsored study in patients with refractory non-Hodgkin lymphoma and multiple myeloma.3 For more information on the clinical study of GDA-201, please visit http://www.clinicaltrials.gov.

GDA-201 is an investigational therapy, and its safety and efficacy has not been established by the U.S. Food and Drug Administration or any other health authority.

About the NAM Therapeutic Platform

Gamida Cells proprietary NAM-based cell expansion platform is designed to enhance the number and functionality of donor cells in culture, enabling the creation of potentially transformative therapies that move beyond what is possible with existing approaches. The NAM therapeutic platform leverages the unique properties of nicotinamide to enable the expansion of multiple cell types including stem cells and natural killer (NK) cells with appropriate growth factors to maintain the cells' original phenotype and potency. This can enable the administration of a therapeutic dose of cells with the potential to improve patient outcomes.

About Gamida Cell

Gamida Cell is an advanced cell therapy company committed to cures for patients with blood cancers and serious blood diseases. We harness our cell expansion platform to create therapies with the potential to redefine standards of care in areas of serious medical need. For additional information, please visit http://www.gamida-cell.com or follow Gamida Cell on LinkedIn or Twitter at @GamidaCellTx.

Cautionary Note Regarding Forward Looking Statements

This press release contains forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995, including with respect to timing of initiation and progress of and data reported from the clinical trials of Gamida Cells product candidates, anticipated regulatory filings, launch readiness and FDA approval, commercialization efforts and Gamida Cells expectations regarding its projected ongoing operating activities, which statements are subject to a number of risks, uncertainties and assumptions, including, but not limited to the scope, progress and expansion of Gamida Cells clinical trials and ramifications for the cost thereof; and clinical, scientific, regulatory and technical developments. In light of these risks and uncertainties, and other risks and uncertainties that are described in the Risk Factors section and other sections of Gamida Cells Annual Report on Form 20-F, filed with the Securities and Exchange Commission (SEC) on February 26, 2020, its Reports on Form 6-K filed with the SEC on May 18, 2020, August 11, 2020 and November 10, 2020, and other filings that Gamida Cell makes with the SEC from time to time (which are available at http://www.sec.gov), the events and circumstances discussed in such forward-looking statements may not occur, and Gamida Cells actual results could differ materially and adversely from those anticipated or implied thereby. Any forward-looking statements speak only as of the date of this press release and are based on information available to Gamida Cell as of the date of this release.

______________________1 Horwitz M.E., Wease S., Blackwell B., Valcarcel D. et al. Phase I/II study of stem-cell transplantation using a single cord blood unit expanded ex vivo with nicotinamide. J Clin Oncol. 2019 Feb 10;37(5):367-374.2 Gamida Cell press release, Gamida Cell Announces Positive Topline Data from Phase 3 Clinical Study of Omidubicel in Patients with High-Risk Hematologic Malignancies, issued May 12, 2020. Last accessed August 31, 2020.3 Clinicaltrials.gov identifier NCT03019666

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Gamida Cell Provides Pipeline Update, Including Detailed Results of Pivotal Phase 3 Clinical Study of Omidubicel, and Prepares to Start BLA Submission...

Bone Marrow Stem Cells Comments Off on Gamida Cell Provides Pipeline Update, Including Detailed Results of Pivotal Phase 3 Clinical Study of Omidubicel, and Prepares to Start BLA Submission… | December 13th, 2020

CAMBRIDGE, Mass.--(BUSINESS WIRE)--HighPassBio, an ElevateBio portfolio company dedicated to advancing novel targeted T cell immunotherapies, today discussed the ongoing Phase 1 trial of the companys lead product candidate, an engineered T cell receptor (TCR) T cell therapy targeting HA-1 expressing cancer cells in an oral presentation at the 62nd American Society of Hematology (ASH) Annual Meeting. The Phase 1 clinical trial, which is being conducted by researchers at Fred Hutchinson Cancer Research Center, is designed to assess the feasibility, safety, and efficacy of this novel cell therapy in the treatment of leukemia following hematopoietic stem cell transplant (HSCT).

The prognosis for leukemia patients whove relapsed or who have residual disease following allogeneic hematopoietic stem cell transplantation is often poor, but we believe that by targeting the minor H antigen, HA-1, through a novel T cell immunotherapy, we can potentially treat and prevent subsequent relapse, said Elizabeth Krakow, M.D., MSc., Assistant Professor, Clinical Research Division, Fred Hutchinson Cancer Research Center, principal investigator of the study, and presenting author. We have observed early promising indicators of anti-leukemic activity following treatment in this trial. We are eager to expand the trial to additional patients as we continue to research the feasibility, safety, and efficacy of this approach.

The abstract for the presentation titled Phase 1 Study of Adoptive Immunotherapy with HA-1-Specific CD8+ and CD4+ Memory T Cells for Children and Adults with Relapsed Acute Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation (HCT): Trial in Progress, can be found on the ASH website under the abstract number 137726.

To date, four patients, including one pediatric patient, have received a total of six infusions in the Phase 1 clinical trial. Patient characteristic data was shared in the oral presentation at ASH, including documented HA-1 TCR T cell persistence in blood and bone marrow up to 18 months. In some patients, clear in vivo anti-leukemic activity was observed at the first dose level, including a subject with aggressive, highly refractory T-ALL and early post-HCT relapse. No significant toxicities attributed to the T cells have been observed, including no infusion reactions or evidence of cytokine release syndrome or graft versus host disease.

The Phase 1 clinical trial is currently recruiting adult and pediatric patients who have residual disease or relapsed leukemia or related conditions following HSCT. As part of the trial, transplant patients and prospective donors may be recruited to participate in the genetic screening portion to determine eligibility. More details are available on clinicaltrials.gov under the study ID number NCT03326921.

About TCR-Engineered T Cell Therapy

A key role of the immune system is to detect tumor antigens, engage T cells, and eradicate the tumor. However, the immune response to tumor antigens varies and is often insufficient to prevent tumor growth and relapse. An approach known as adoptive T cell therapy, using T cell receptors, or TCRs, can overcome some of the obstacles to establishing an effective immune response to fight off the target tumor. TCRs are molecules found on surface of T cells that can recognize tumor antigens that are degraded to small protein fragments inside tumor cells. Unlike CAR T cells that recognize only surface antigens, TCRs can recognize small protein fragments derived from intracellular and surface antigens offering a more diverse way to attack tumors. These small protein fragments show up on the tumor cell surface, with another protein called major histocompatibility complex (MHC), that are recognized by the TCRs and consequently signal the bodys immune system to respond to fight off and kill the tumor cells.

Tumor-specific TCRs can be identified and then engineered into T cells that recognize and attack various types of cancers, representing a novel approach to treating and potentially preventing disease.

Adoptive T cell therapy can be applied to tackling relapse of leukemia post hematopoietic stem cell transplant (HSCT) by targeting the antigens expressed only by the patients native cells, and not by the cells from the stem cell transplant donor. HA-1, a known minor histocompatibility antigen, is expressed predominantly or exclusively on hematopoietic cells, including leukemic cells. There is evidence that T cells specific for HA-1 can induce a potent and selective antileukemic effect. HA-1 TCR T cell therapy is a new investigational immunotherapy for the management of post transplantation leukemia relapse.

About Leukemia post HSCT Treatment and the Risk of Relapse

Leukemia, a cancer of the blood or bone marrow characterized by an abnormal proliferation of blood cells, is the tenth most common type of cancer in the U.S. with an estimated 60,140 new cases and 24,400 deaths in 2016. Leukemia arises from uncontrolled proliferation of a specific type of hematopoietic (blood) cell that is critical for a functional immune system. As a result, when patients are given very high doses of chemotherapy to eradicate leukemic cells, most normal cells are killed as well, necessitating a transplant of hematopoietic stem cells from a donor to reconstitute the patients bone marrow and circulating hematopoietic cells. In some cases, the transplanted T cells from the donor can also recognize and eliminate the hematopoietic cells, including leukemia, from the recipient, thus preventing relapse. This can be described as a graft versus leukemia effect. Other hematologic disorders related to leukemia, like myelodysplastic syndrome (MDS), can also be treated in this way.

While HSCT can be curative, it is estimated that 25-50 percent of HSCT recipients relapse; leukemia relapse remains the major cause of allogeneic HSCT failure, and the prognosis for patients with post-HCT relapse is poor. Relapse occurs following allogeneic HSCT in approximately one-third of patients with acute leukemia who undergo the procedure, and most patients subsequently die of their disease.

About HighPassBio

HighPassBio, an ElevateBio portfolio company, is working to advance a novel approach to treating hematological malignancies by leveraging T cell receptor (TCR)-engineered T cells, known as TCR T cells. The companys lead program is designed to treat or potentially prevent relapse of leukemia in patients who have undergone hematopoietic stem cell transplant (HSCT). The technology was born out of research conducted at Fred Hutchinson Cancer Research Center by world renowned expert, Dr. Marie Bleakley.

About ElevateBio

ElevateBio, LLC, is a Cambridge-based creator and operator of a portfolio of innovative cell and gene therapy companies. It begins with an environment where scientific inventors can transform their visions for cell and gene therapies into reality for patients with devastating and life-threatening diseases. Working with leading academic researchers, medical centers, and corporate partners, ElevateBios team of scientists, drug developers, and company builders are creating a portfolio of therapeutics companies that are changing the face of cell and gene therapy and regenerative medicine. Core to ElevateBios vision is BaseCamp, a centralized state-of-the-art innovation and manufacturing center, providing fully integrated capabilities, including basic and translational research, process development, clinical development, cGMP manufacturing, and regulatory affairs across multiple cell and gene therapy and regenerative medicine technology platforms. ElevateBio portfolio companies, as well as select strategic partners, are supported by ElevateBio BaseCamp in the advancement of novel cell and gene therapies.

ElevateBios investors include F2 Ventures, MPM Capital, EcoR1 Capital, Redmile Group, Samsara BioCapital, The Invus Group, Surveyor Capital (A Citadel company), EDBI, and Vertex Ventures.

ElevateBio is headquartered in Cambridge, Mass, with ElevateBio BaseCamp located in Waltham, Mass. For more information, please visit http://www.elevate.bio.

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ElevateBio's HighPassBio Presents on Novel T Cell Receptor Cell Therapy for Leukemia Relapse at 62nd Annual ASH Meeting - Business Wire

Bone Marrow Stem Cells Comments Off on ElevateBio’s HighPassBio Presents on Novel T Cell Receptor Cell Therapy for Leukemia Relapse at 62nd Annual ASH Meeting – Business Wire | December 13th, 2020

NEW YORK, Dec. 7, 2020 /PRNewswire/ --Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) ("Actinium" or the "Company") today announced that safety data from its ongoing pivotal Phase 3 SIERRA trial of Iomab-B in patients with relapsed or refractory Acute Myeloid Leukemia (R/R AML) were presented at the 2020 American Society of Hematology (ASH) annual meeting. The oral presentation highlighted Iomab-B's targeting ability and corresponding safety data from 110 patients from the SIERRA trial for which detailed safety data was available. Iomab-B targets CD45, an antigen expressed on leukemia and lymphoma cancer cells and immune cells including bone marrow stem cells but not cells outside of the blood forming or hematopoietic system. This allows high amounts of radiation to be delivered to the bone marrow via Iomab-B while sparing healthy organs. As a result, statistically significant lower rates of sepsis were reported as well as lower rates of febrile neutropenia, mucositis and non-relapse transplant related mortality in patients receiving Iomab-B and bone marrow transplant (BMT) compared to patients that received salvage therapy and a BMT. In addition, patients that crossed over to receive Iomab-B and went to BMT after receiving salvage therapy but not achieving a complete response also had lower rates of sepsis, febrile neutropenia, mucositis and non-relapse transplant related mortality.

Dr. Mark Berger, Actinium's Chief Medical Officer, commented, "We are pleased that the engraftment and safety profile of Iomab-B remains positive and consistent with prior interim safety results at 75% of patient enrollment in SIERRA and also consistent with the large body of historical data from Iomab-B. Collectively, this data gives excitement as we approach the upcoming ad hoc interim analysis for SIERRA that will be completed by year-end and the ultimate potential of Iomab-B for patients with R/R AML and other blood cancers as a targeted conditioning regimen."

Safety data presented in ASH oral presentation are highlighted in the table below:

ASH Oral Presentation:High Doses of Targeted Radiation with Anti-CD45 Iodine (131I) Apamistamab [Iomab-B] Do Not Correlate with Incidence of Mucositis, Febrile Neutropenia or Sepsis in the Prospective, Randomized Phase 3 Sierra Trial for Patients with Relapsed or Refractory Acute Myeloid Leukemia

Adverse Event

Received Iomab-B/HCT (N=47)1% (N)

No CR Crossed over to Iomab-B/HCT (N=30)2% (N)

Achieved CR and received Std HCT (N=9) % (N)

Sepsis

4.3 (2)

22.2 (6)

33.3 (3)

Febrile Neutropenia Gr 3-4

34.8 (16)

40.7 (11)

55.6 (5)

Mucositis Gr 3-4

10.9 (5)

18.5 (5)

33.3 (3)

Day +100 Non-Relapse Mortality3

2/45

(4.4%)

3/26

(11.5%)

2/9

(22.2%)

1 Adverse Event data available for 46 of 47 evaluable patients

2 Adverse Event data available for 27 of 30 evaluable patients

3 Iomab-B arm: 4 patients unevaluable. Conventional Care Arm: 4 patients unevaluable

Patient Group

No. of Patients

Radiation dose delivered to the Marrow. Median (range)

Radiation dose to GI tract. Median (range)

Iomab-B

47

14.9 Gy

(4.6-32)

2.8 Gy

(1.6-6.7)

Vijay Reddy, Vice President, Clinical Development and Head of BMT, "The targeted nature of Iomab-B makes it highly differentiated from current BMT conditioning regimens that are largely comprised of non-targeted cytotoxic chemotherapies. These data from SIERRA showing higher rates of sepsis, neutropenia and mucositis in patients receiving chemotherapy are consistent with the literature and unfortunately what we expected but hope to address with Iomab-B. Particularly, chemotherapy's effect on the GI tract and resulting mucositis, which we believe is leading to the higher rates of sepsis seen in the control arm. We are highly encouraged by the lower rates of adverse events and the universal engraftment reported from SIERRA and excited for the potential of targeted conditioning could have an BMT access, patient outcomes and quality of life."

About Iomab-B

Iomab-B (I-131 apamistamab) via the monoclonal antibody apamistamab, targets CD45, an antigen widely expressed on leukemia and lymphoma cancer cells, B cells and stem cells. Apamistamab is linked to the radioisotope iodine-131 (I-131) and once attached to its target cells emits energy that travels about 100 cell lengths, destroying a patient's cancer cells and ablating their bone marrow. By carrying iodine-131 directly to the bone marrow in a targeted manner, Actinium believes Iomab-B will avoid the side effects of radiation on most healthy tissues while effectively killing the patient's cancer and marrow cells.

Iomab-B is currently being studied in the pivotal Phase 3 SIERRA (Study of Iomab-B in Relapsed or Refractory AML) trial, a 150-patient, randomized controlled clinical trial in patients with relapsed or refractory Acute Myeloid Leukemia (AML) who are age 55 and above. The SIERRA trial is being conducted at preeminent transplant centers in the U.S. with the primary endpoint of durable Complete Remission (dCR) at six months and a secondary endpoint of overall survival at one year. Upon approval, Iomab-B is intended to prepare and condition patients for a bone marrow transplant, also referred to as a hematopoietic stem cell transplant, in a potentially safer and more efficacious manner than the non-targeted intensive chemotherapy conditioning that is the current standard of care in bone marrow transplant conditioning. A bone marrow transplant is often considered the only potential cure for patients with certain blood-borne cancers and blood disorders. Additional information on the Company's Phase 3 clinical trial in R/R can be found at http://www.sierratrial.com.

About Actinium Pharmaceuticals, Inc. (NYSE: ATNM)

Actinium Pharmaceuticals, Inc. is a clinical-stage biopharmaceutical company developing ARCs or Antibody Radiation-Conjugates, which combine the targeting ability of antibodies with the cell killing ability of radiation. Actinium's lead application for our ARCs is targeted conditioning, which is intended to selectively deplete a patient's disease or cancer cells and certain immune cells prior to a BMT or Bone Marrow Transplant, Gene Therapy or Adoptive Cell Therapy (ACT) such as CAR-T to enable engraftment of these transplanted cells with minimal toxicities. With our ARC approach, we seek to improve patient outcomes and access to these potentially curative treatments by eliminating or reducing the non-targeted chemotherapy that is used for conditioning in standard practice currently. Our lead product candidate, I-131 apamistamab (Iomab-B) is being studied in the ongoing pivotal Phase 3 Study of Iomab-B in Elderly Relapsed or Refractory Acute Myeloid Leukemia (SIERRA) trial for BMT conditioning. The SIERRA trial is over seventy-five percent enrolled and positive single-agent, feasibility and safety data has been highlighted at ASH, TCT, ASCO and SOHO annual meetings. More information on this Phase 3 clinical trial can be found at http://www.sierratrial.com. I-131 apamistamab will also be studied as a targeted conditioning agent in a Phase 1 study with a CD19 CAR T-cell therapy and in a Phase 1/2 anti-HIV stem cell gene therapy with UC Davis. In addition, we are developing a multi-disease, multi-target pipeline of clinical-stage ARCs targeting the antigens CD45 and CD33 for targeted conditioning and as a therapeutic either in combination with other therapeutic modalities or as a single agent for patients with a broad range of hematologic malignancies including acute myeloid leukemia, myelodysplastic syndrome and multiple myeloma. Ongoing combination trials include our CD33 alpha ARC, Actimab-A, in combination with the salvage chemotherapy CLAG-M and the Bcl-2 targeted therapy venetoclax. Underpinning our clinical programs is our proprietary AWE (Antibody Warhead Enabling) technology platform. This is where our intellectual property portfolio of over 130 patents, know-how, collective research and expertise in the field are being leveraged to construct and study novel ARCs and ARC combinations to bolster our pipeline for strategic purposes. Our AWE technology platform is currently being utilized in a collaborative research partnership with Astellas Pharma, Inc. Website: http://www.actiniumpharma.com

Forward-Looking Statements for Actinium Pharmaceuticals, Inc.

This press release may contain projections or other "forward-looking statements" within the meaning of the "safe-harbor" provisions of the private securities litigation reform act of 1995 regarding future events or the future financial performance of the Company which the Company undertakes no obligation to update. These statements are based on management's current expectations and are subject to risks and uncertainties that may cause actual results to differ materially from the anticipated or estimated future results, including the risks and uncertainties associated with preliminary study results varying from final results, estimates of potential markets for drugs under development, clinical trials, actions by the FDA and other governmental agencies, regulatory clearances, responses to regulatory matters, the market demand for and acceptance of Actinium's products and services, performance of clinical research organizations and other risks detailed from time to time in Actinium's filings with the Securities and Exchange Commission (the "SEC"), including without limitation its most recent annual report on form 10-K, subsequent quarterly reports on Forms 10-Q and Forms 8-K, each as amended and supplemented from time to time.

Contacts:

Investors:Clayton Robertson Actinium Pharmaceuticals, Inc. [emailprotected]

Hans Vitzthum LifeSci Advisors, LLC[emailprotected](617) 430-7578

SOURCE Actinium Pharmaceuticals, Inc.

http://www.actiniumpharma.com/

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Actinium Highlights Iomab-B Safety Data Presented at the 62nd American Society of Hematology Annual Meeting - PRNewswire

Bone Marrow Stem Cells Comments Off on Actinium Highlights Iomab-B Safety Data Presented at the 62nd American Society of Hematology Annual Meeting – PRNewswire | December 13th, 2020

What started out as a journey to better understand regulatory T cells has now led to an intriguing approach with an investigational cell therapy designed to prevent the risk of graft-versus-host disease (GVHD) and to improve relapse-free survival rates in patients undergoing hematopoietic stem cell transplantation (HSCT).

Data of a phase 1/2 trial recently showed that the first-generation precision cell treatment Orca-T compared with a historical control of standard HSCT demonstrated faster neutrophil (median, 12 days vs 14 days; P < .0001) and platelet engraftment (median, 11 days vs 17 days; P < .0001), decreased incidence of grade 2 or higher GVHD at 100 days (10% vs 30%, P = .005) and chronic GVHD at 1 year (3% vs 46%, P = .0002).1,2

The 1-year GVHD-free and GVHD relapse-free survival (GRFS) rates were 75% with the use of Orca-T vs 31% with standard HSCT (P < .0001). The comparator cohort was derived from contemporaneous patients who had been treated at Stanford University with a conventional allograft.

Along with feasibility of the approach, the results also highlight how Orca-T demonstrates potent anti-leukemic activity in patients who have active disease at HSCT, which suggests that the decrease of GVHD does not impact graft-vs-leukemia (GvL).

That is the most exciting part about the Orca-T story; it is the ability to do this with precision, with speed, and to export it to other sites. The results are intriguing, and very supportive, said Robert Negrin, a professor of medicine (blood and marrow transplantation), and chief of the Division of Blood and Marrow Transplantation at Stanford University.

In an interview with OncLive, Negrin, who is senior author on the trial, shared the evolution of Orca-T as a novel approach to HSCT, highlighted his robust experience with using this cell therapy at Stanford University, and how Orca-T is a potential prevention method for GVHD.

OncLive: Please provide some background to this therapeutic approach. What is the mechanism of action? How is it effective in patients undergoing transplant?

Negrin: This whole idea came from mouse studies many, many years ago, where we identified GVHD as being a dysregulated immune reaction that just keeps going, and going, and going. Like you and I, when we react to something, we have a reactionlet's say, influenza. Our body responds, and then we stop reacting and you get better. With GVHD, what we noticed in using a bioluminescent animal model is that the alloreactive T cells just keep going, going, and going and are unrelenting in mice, just like in people. The problem is very similar and affects certain organs in a very similar way.

Therefore, we went about trying to understand the use of so-called regulatory cells. These are cells that everybody has that help control immune reactions. We just applied them in this clinical scenario, first in mice work done by Matthias Edinger, MD, when he was a postdoctoral fellow many years ago [and other researchers]. All of them were very actively involved in these studies, and showed, somewhat surprisingly, that the administration of regulatory T cells could control this dysregulated immune response that we called GVHD.

Probably more surprising was that, at least in the animal models, it also allowed for the benefits of transplant, namely, the graft-vs-tumor effect and better immune recovery. This was in large part because GVHD also impacts the immune repertoire and where the immunity is developed in the recipient.

All of this was very nice in mouse models and was very elegant. We did a lot of studies, published a number of nice papers, and thought this would be a great idea because it sort of solved, or at least addressed, the principal problems after bone marrow transplantationnamely, avoidance of GVHD yet retention of graft-versus-tumor effects and better immunity. A lot of times, people say, "Oh, that sounds good in mice, but, that's too good to be true." And, theyll ask, "Will that all work in people?"

Where did the biggest challenges lie in this approach?

The big challenge came about to try to apply this to patients. We also have one other interesting point that is relevant. If we gave the regulatory T cells first, before the so-called conventional CD4+/CD8+ cells, that allowed for a lower dose of regulatory T cells. This is because a big challenge is the paucity of these cells; you and I don't have that many.

Then, the other big challenge was the technical ability to isolate in cells. What we do in mice is cell sorting, which is a standard technology. But, that was not developed in people because we're bigthere are a lot of cells, and cell sorting is rather slow, and it's very specific. To get enough cells takes a really long time. It's somewhat of a heroic thing to do in people, to get the adequate amount ourselves; of course, we don't really know what this proper cell dose is.

However, what we thought we learned was that the ratio of conventional to regulatory T cells was the key component. Also, if you give the regulatory T cells first, you can get fewer numbers. Those are things you can do in transplant. You can get the cell from the donor, and you can give cells in a certain sequence; all of those things are very doable. It seemed like an attractive thing to do in patients.

Then, the question was: Does it work? There are 3 groups that have really pioneered this work. The first study came from the University of Perugia in Italy. They did this in haploidentical transplantation; you cannot avoid immunosuppression in haploidentical transplants. They were able to show in several nice papers that you could do this strategy, and seemingly, get away with low risk of GVHD, and also low relapse. This is because the other issue is: how do you measure the graft-vs-tumor effect? There is no assay, and we have no test; you have to wait and see who relapses and who doesn't. Therefore, they also showed rather convincingly that you could reduce GVHD risk, yet, there was a very low risk of relapse in their high-risk patient population. Those were very important [data].

Another study from the University of Minnesota did this with umbilical cord blood. They expanded the regulatory T cells from a third cord blood unit, which is somewhat heroicit is another level of complexity to isolate the cells and then expand them. We did this in matched donorseither matched siblings or matched unrelated donors. We published a paper in JCI Insight several years ago showing the initial results, and they look quite favorable.

Therefore, what I think is most exciting about what Orca Bio has done is they are developing technology to isolate the cells more quickly, to be able to do this on a clinical scale, with precision, and with speed. Also, [they are developing the technology] to be able to distribute it to anybody, because the criticism of all these studies is that, "Oh, that's nice. But, this is a single-institution study. Is this really true? Can this be exported? Could this be something that [an organization] other than these [individual] centers are really focused in this area and have developed these technologies could really do? Orca Bio is developing the technology, and improving the technology, because it's still very cumbersome, and exporting the technology so that you could do this, theoretically, at any center.

That's what I think is most exciting about the Orca Bio abstract; it is demonstrating that this can be done. It certainly opens the door to prevention of GVHD. As we move into an era of using cell-based therapeutics, now, this opens up many other possibilities, because you use these regulatory cells and autoimmune disorders and organ transplant tolerance. There are many other cell types that have potential clinical utility, but getting them, and purifying them, is a big challenge. There are many other possibilities that one could think of.

Obviously, more time will be required to follow these patients, but they certainly are supportive of the idea that you can improve overall outcomes using this strategy. That's what we hope to be able to demonstrate further.

Please focus on the scalability of this approach. Through these types of collaborations, how do you see Orca-T potentially moving through the FDA pipeline?

In academia, we don't develop drugs. It's too much, we don't have the resources, we don't have the capability, and we don't have the monitoring capability that is required for multi-institutional studies. Where these commercial partners come in is, they can raise money for interesting concepts, which Orca Bio has done, and they can export this to other centers, and that's critically important.

As we've seen in the CAR T-cell [therapy] world, that can be a quite successful commercial business. Also going through the process of an FDA approvalwhich Orca Bio is moving along in that processand getting the right designations is critically important to commercial entities. In academia, it's important to us, but that's just not our focus.

We don't have the resources around, the people and the expertise to really drive things through that process. We're good at developing the studies and getting FDA approvals, and [investigational new drug applications], but not really [good at] developing drugs as a commercial entity. This collaboration is key to doing this successfully; for example, at Orca Bio, [they have] technology to separate cells more efficiently and effectively. They also have the resources to do a multi-institutional clinical trial, and the expertise to move something through and present it to the FDA. Those are key components.

Could you expand on the study and respective data from this phase 1/2 trial?

Here at Stanford Cancer Institute, we did find in our patients that giving low doses of immunosuppressive medications with a single agent seem to improve the outcomes, and it's remarkable how well these patients have gone through the transplant. It's a little bit hard to appreciate an abstract until you take care of these patients, and many of them just sort of move to the transplant with relatively little challenges. We have not seen greater risks of things like infection [or] disease recurrence; those are obviously things that will be followed.

When we look at the 1-year GVHD relapse-free survival rate, which is an endpoint that most transplant studies would agree is the most important end point, the overall outcomes are much more favorable compared with a historical control group.

The data are very encouraging, and the overall outcomes look very strong in a reasonable number of patients now. We think it's important for the community to hear about it, and to get it on everybody's radar, and be excited about trying to move this forward as a more standard therapy. This is still a clinical trial, so it's not, it's not part of any standard therapies yet. We are using this quite regularly and have been very encouraged by the ease of which patients go through the transplant. It's still an allogeneic transplant; there still are many challenges there. However, these patients seem to be doing quite well, we're very encouraged, and so we keep going.

How does this approach impact patient outcomes as it relates to quality of life (QoL)?

The hard end points of 1-year relapse-free survival is obviously the most important to patients. However, going through an allogeneic transplant is obviously an incredibly difficult thing. Fortunately, I've only seen it [from] the doctor side, not [as a] patient.

However, I've seen many, many patients, and the quality of their life as they go through this experience is very important to all of us. As we saw these patients go through these studies, we felt like we were capturing something that was really important, and that is the ease [at which] many patients went through this experience, which just seemed different. It's hard to capture that.

It's really important for patients to speak and, and the way patients speak is in different ways. One way is through the QoL measures that they answer. This is [what they find] important, this is what they experiencednot what we say is happening. That's really important to hear that voice too. Those are data we're trying to collect. It's not so easy, because going through a bone marrow transplant is a poor QoL for everybody. But, by just to trying to capture this, [Orca-T seems] better than what we what we thought.

How has this changed the mindset of cell-based approaches in the community?

What has changed is the belief in the concept of cell-based therapies. A lot of these things are somewhat fanciful. It is also important to show that we can translate from an animal model [to a human]. There is a lot of criticism of animal modeling, because people say, "Well, it's nice for animal models, but it doesn't really translate into the clinic." Actually, my view is that because we don't actually follow the animal models, there are many compromises one needs to make. When you translate studies from animals to humans, there are many differences, and it's really important to try to follow them as carefully as you can within the limitations of what is possible. We were very engaged in that and tried to follow as carefully as we could. To me, that is very encouragingthat you can study things in animals that generate new concepts and be able to translate that into a clinical trial.

Obviously, with all of the caveats of an early-phase clinical trial, more time needs to pass, more patients to be treated, and you need to export [the treatment] to other centers. That's a really important point, because there are many things that get lost because, "it's too complicated. It's too expensive. People can't do it." I don't think anybody can do high-speed cell sorting, as a clinical project in a standard or standard cell-processing laboratory. It's above the level of what most processing laboratories can do.

References

Excerpt from:
Negrin Shines Light on the Orca-T Story in GVHD - OncLive

Bone Marrow Stem Cells Comments Off on Negrin Shines Light on the Orca-T Story in GVHD – OncLive | December 13th, 2020

In the first study, researchers used CRISPR/Cas9 to treat two inherited blood disorders, beta thalassemia and sickle cell disease (SCD). The trial, which demonstrated remarkable improvements in all participants, is the first time this revolutionary approach has been used successfully in these patient populations.

Given that the only FDA-approved cure for sickle cell disease, a bone marrow transplant, is not widely accessible, having another curative option would be life-changing for a large number of the sickle cell disease population, said press briefing moderator, Dr Catherine Bollard, of Childrens National Research Institute and George Washington University. While longer follow-up data are needed, this study is extremely exciting for the field.

Investigators reported interim safety and efficacy data from 10 patients who received an investigational gene-editing based therapy, CTX001. The trials are the first to test a CRISPR-Cas9 gene editing therapy in humans for a genetic disease, the researchers reported.

Sickle cell disease (SCD) can cause a variety of health problems including episodes of severe pain, called vaso-occlusive crises, as well as organ damage and strokes, while patients with transfusion-dependent thalassemia (TDT) are dependent on blood transfusions from early childhood.The only available cure for both diseases is a bone marrow transplant from a closely related donor, an option that is not available for the vast majority of patients because of difficulty locating matched donors, the cost, and the risk of complications.

In the studies, the researchers goal is to functionally cure the blood disorders using CRISPR/Cas9 gene-editing by increasing the production of fetal hemoglobin, which produces normal, healthy red blood cells as opposed to the misshapen cells produced by faulty hemoglobin in the bodies of individuals with the disorders.

The clinical trials involve collecting stem cells from the patients. Researchers edit the stem cells using CRISPR-Cas9 and infuse the gene-modified cells into the patients. Patients remain in the hospital for approximately one month following the infusion.

Prior to receiving their modified cells, the seven patients with beta thalassemia required blood transfusions around every three to four weeks and the three patients with SCD suffered episodes of severe pain roughly every other month.

All the individuals with beta thalassemia have been transfusion independent since receiving the treatment, a period ranging between two and 18 months. Similarly, none of the individuals with SCD have experienced vaso-occlusive crises since CTX001 infusion.

All patients showed a substantial and sustained increase in the production of fetal hemoglobin.

Researchers report that the safety of CTX001 infusion was generally consistent with the chemotherapy regimen received prior to cell infusion.

Four serious adverse events (SAEs) related or possibly related to CTX001 were reported in one patient with TDT: headache, haemophagocytic lymphohistiocytosis (HLH), acute respiratory distress syndrome, and idiopathic pneumonia syndrome. All four of these SAEs occurred in the context of HLH and were either resolved or clinically improving at the time of this analysis. No other CTX001-related SAEs were reported in the other patients with TDT or in any patients with SCD, said the investigators.

Haydar Frangoul, MD, Medical Director of Pediatric Hematology and Oncology at Sarah Cannon Research Institute, HCA Healthcares TriStar Centennial Medical Center, said:What we have been able to do through this study is a tremendous achievement. By gene editing the patients own stem cells we may have the potential to make this therapy an option for many patients facing these blood diseases.

Because of the precise way CRISPR-Cas9 gene editing works, Dr Frangoul suggested the technique could potentially cure or ameliorate a variety of diseases that have genetic origins.

The trial was sponsored by CRISPR Therapeutics and Vertex Pharmaceuticals.

The second two studies indicate new opportunities to reach a broader patient population with chimeric antigen receptor T-cell (CAR-T) therapy, which has been shown to be effective in some blood cancers but does not work in all patients.

One of the new studies offers an explanation as to why some patients do not respond to CD19-CAR-T therapy and suggests a way to overcome this resistance. The other study suggests CD19-CAR-T may be a viable option for some patients with high-risk non-Hodgkin lymphoma who have not responded to standard treatments.

Getting more data on CD19-CAR-T therapy in the high-risk non-Hodgkin lymphoma population is very important, said Dr Bollard. We know that CD19-CAR-T therapy does not work for some patients, so these studies underscore the need to better understand the immune evasion mechanisms T cells might be susceptible to and not just focus on their role as a vehicle for the CAR. Doing so may improve our capacity to administer effective T-cell immunotherapies.

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ASH virtual event hears about CRISPR and CAR-T based approaches to hard-to-treat blood disorders and cancers - BioPharma-Reporter.com

Bone Marrow Stem Cells Comments Off on ASH virtual event hears about CRISPR and CAR-T based approaches to hard-to-treat blood disorders and cancers – BioPharma-Reporter.com | December 13th, 2020

WASHINGTON, Dec. 8, 2020 /PRNewswire/ --Genetic mutations linked with cancer can occur during childhood or even before birth and proliferate in the body for many years before causing cancer symptoms, according to a new study. The study, which traced the genetic origins of a blood cancer in 10 individuals, suggests there may be untapped opportunities to detect cancer warning signs much earlier and potentially intervene to prevent or slow cancer development.

"Our preliminary findings show these cancer driver mutations were often acquired in childhood, many decades before the cancer diagnosis," said senior study authorJyoti Nangalia, MD,of the Wellcome Sanger Institute and University of Cambridge. "Our results finally answer the common question posed by patients, 'How long has this cancer been growing?' as we were able to study how these particular cancers developed over the entire lifetime of individual patients."

The researchers analyzed bone marrow and blood samples from 10 people with Philadelphia-negative myeloproliferative neoplasms, a type of cancer that causes stem cells in the bone marrow to produce too many blood cells. In the majority of patients, this cancer is driven by a genetic mutation called JAK2V617F. By assessing JAK2V617F, other cancer-linked mutations and hundreds of thousands of other mutations that a person naturally acquires throughout life, the researchers were able to trace the ancestry of different blood cells and estimate the time at which each patient acquired JAK2V617F and other important mutations.

They determined that, in these 10 patients, the first cancer-linked mutations emerged as early as a few weeks after the start of life and up to the first decade of childhood despite clinical disease presenting many decades later in life.

"We were not expecting this," said Dr. Nangalia. "In fact, in one patient, the JAK2 mutation was acquired more than 50 years before their diagnosis."

While it is often assumed that most cancers are diagnosed within a few years of their emergence, the findings point to a more gradual, lifelong process in which a single cell acquires a cancer-linked mutation early in life and then slowly grows over decades, ultimately leading to cancer.

"Some of these cancer-linked mutations are found in healthy individuals as we get older, suggesting that aging causes them," said Dr. Nangalia. "However, aging per se doesn't drive such growth it simply takes a long time for the clones to grow." Sometimes, the growing clones pick up additional cancer-linked mutations along the way, accelerating their growth, researchers found.

"For these patients, we calculated how many of these cancer clones would have been present in the past, and our results suggest that these clones may have been detectable up to 10 to 40 years before diagnosis," said Dr. Nangalia. "In addition to detecting the mutations, the rate at which the mutated clones grew was also very important in determining whether, and when, cancer develops." The findings suggest that genetic testing could help identify people at risk for cancer much earlier than current methods allow, according to researchers.

The next steps would be to understand the factors that influence the different rates of cancer growth and determine whether there could be ways to intervene and slow the growth of cells with cancer-linked mutations. The researchers say their method for pinpointing the origin of this blood cancer could also be applied to other mutations and other blood cancers. "Understanding the timelines of development of different cancers is critical for efforts aimed at early cancer detection and prevention," said Dr. Nangalia.

Jyoti Nangalia, MBBChir,Wellcome Sanger Institute and University of Cambridge, will present this study during the Late-Breaking Abstracts session on Tuesday, December 8 at 7:00 a.m. Pacific time on the ASH annual meeting virtual platform.

For the complete annual meeting program and abstracts, visit http://www.hematology.org/annual-meeting. Follow ASH and #ASH20 on Twitter, Instagram, LinkedIn, and Facebook for the most up-to-date information about the 2020 ASH Annual Meeting.

The American Society of Hematology (ASH) (www.hematology.org) is the world's largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood. For more than 60 years, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology. ASH publishes Blood (www.bloodjournal.org), the most cited peer-reviewed publication in the field, and Blood Advances (www.bloodadvances.org), an online, peer-reviewed open-access journal.

SOURCE American Society of Hematology

http://www.hematology.org

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Researchers Trace the Origin of Blood Cancer to Early Childhood, Decades before Diagnosis - PRNewswire

Bone Marrow Stem Cells Comments Off on Researchers Trace the Origin of Blood Cancer to Early Childhood, Decades before Diagnosis – PRNewswire | December 13th, 2020

Joceline Colvert was diagnosed with relapsing remitting Multiple Sclerosis in her early 20s and says she spent the first eight years researching and managing her condition while trying to mention it as little as possible to others and completing her Sound Production degree.

I spent most of my late 20s and early 30s finding ways to manage relapses, the symptoms of which have included whole body numbness, loss of the use of both hands, right eye blindness, vertigo and double vision, she said. Thankfully these symptoms did resolve however left scarring on my nerves. This results in reduced vision in my formerly blind eye and hands that dont function very well with repetitive tasks.

This semi-denial worked for me until about 2010 when I started to become a bit limpy which I did my best to hide. After a couple of memorable falls and fractures I decided to face up to being slightly rickety and got a hiking pole that I used occasionally in public. Since then Ive needed to get used to being visibly disabled, and switch between two hiking poles for very short distances and a wheelchair everywhere else.

Joceline, who lives with her husband and her five beloved cats and dogs, says she is not eligible for Haematopoietic Stem Cell Transplantation (HSCT), on the NHS which is the first treatment I have ever got excited about and believe could work. It could be truly life-changing.

As a result she is trying to raise money to fund the treatment herself.

HSCT is a procedure that aims to reset the faulty immune system which, in my case, is attacking my nervous system from within, Joceline said. Stem cells will be taken from my bone marrow or blood before my immune system is wiped out with chemotherapy. My cells are then reintroduced into my blood, where they grow a new immune system which will hopefully no longer attack my nerves or have any memory of MS.

The aim of HSCT is to completely halt progression, putting MS into remission with no requirement for immunosuppressant drug therapy. The success rate for relapsing remitting MS is 80% - 90% which is absolutely phenomenal compared to the limited available drug treatments, which only aim to slow down disability.

HSCT is available on the NHS, however there is a very strict criteria for which I do not qualify. The expense of the treatment and the increased pressures on the public purse mean the NHS will only treat patients who have been diagnosed for fewer than 15 years.

I have been diagnosed for 18 years.

I had prepared myself for this possibility and, for the last year, have been researching treatment with The National Pirogov Medical Centre Russia (Moscow). Russia has been pioneering in their use of HSCT to treat MS and are world renowned for their expertise and care. Im excited to have a treatment date in March 2021 which fills me with hope for a future free from progression. I need your help to get there.

Joceline, who loves making stop-motion animation puppets and props and playing musical instruments, says the treatment will cost 40,800, and the flights 800.

She has launched a Go Fund Me page at https://gf.me/u/y538k2 which has already seen donations of more than 26,000.

I am incredibly grateful for any help you can give towards enabling me to access this life-changing treatment, she said.

After almost two decades of managing MS flare-ups and their consequences, its hard to put into words just what a future without them would mean to me.

Thank you for reading this and for any help you can put towards this goal.

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Haywards Heath woman's bid to fund stem cell treatment to combat MS - Mid Sussex Times

Bone Marrow Stem Cells Comments Off on Haywards Heath woman’s bid to fund stem cell treatment to combat MS – Mid Sussex Times | December 13th, 2020

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Magenta Therapeutics (NASDAQ: MGTA), a clinical-stage biotechnology company developing novel medicines to bring the curative power of stem cell transplant to more patients, today announced final clinical results from its earlier completed Phase 1 clinical trial as well as development updates for its MGTA-145 stem cell mobilization therapy, including commencement of enrollment in a Phase 2 clinical trial in multiple myeloma, and its plans for a Phase 2 clinical trial in allogeneic stem cell transplant for patients with acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL) and myelodysplastic syndrome (MDS). The company also previously announced a clinical collaboration with bluebird bio to evaluate MGTA-145 for mobilizing and collecting stem cells in adults and adolescents with sickle cell disease (SCD). Additional preclinical results were also presented at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, taking place virtually from December 5-8, 2020, on the Magenta conditioning platform, including MGTA-117 program, which is a targeted antibody-drug conjugate (ADC) to prepare patients for stem cell transplant.

MGTA-145 Advancement to Phase 2 Development in Blood Cancers

The company announced that enrollment has started and is ongoing in a Phase 2 clinical trial of MGTA-145, used in combination with plerixafor, to mobilize and collect stem cells for autologous stem cell transplantation of multiple myeloma patients at Stanford University. Magenta expects that this trial will provide patient-level data on stem cell mobilization and collection, characteristics of the mobilized graft and engraftment in patients with multiple myeloma.

Additionally, through a collaboration with the National Marrow Donor Program/Be The Match, a global leader in facilitating allogeneic hematopoietic stem cell transplantation, Magenta plans to initiate a Phase 2 clinical trial in early 2021 using MGTA-145 to mobilize and collect stem cells from allogeneic donors for transplant in patients with AML, ALL and MDS. Allogeneic stem cell transplant provides a potentially curative therapeutic option for patients with these diseases. This clinical trial will evaluate stem cell mobilization, collection, cell quality, engraftment and the potential for reduced Graft-versus-Host Disease (GvHD), which is of particular importance in the allogeneic transplant setting.

MGTA-145 in Sickle Cell Disease

Magenta Therapeutics recently announced an exclusive clinical collaboration with bluebird bio to evaluate the utility of MGTA-145, in combination with plerixafor, for the mobilization and collection of stem cells in adults and adolescents with SCD.

The data from this clinical trial could provide proof-of-concept for MGTA-145, in combination with plerixafor, as the preferred mobilization regimen for patients with SCD. bluebird bios experience with plerixafor as a mobilization agent in SCD aligns with Magentas combination therapy approach, utilizing MGTA-145 plus plerixafor with potential for safe, rapid and reliable mobilization of sufficient quantities of high-quality stem cells to improve outcomes associated with stem cell transplantation.

MGTA-145 Presentations at ASH

Magenta presented final clinical data from its MGTA-145 stem cell mobilization Phase 1 clinical trial in healthy volunteers at the ASH Annual Meeting. All primary and secondary endpoints were met in the study completed earlier this year.

The results demonstrate that a single dose of MGTA-145, in combination with plerixafor, rapidly and reliably mobilized high numbers of stem cells in a single day without the need for G-CSF for potential use in diseases that can benefit from autologous and/or allogeneic stem cell transplantation. The additional data also offer further confirmation that MGTA-145, in combination with plerixafor, was well tolerated and provides a rapid and reliable method to obtain large numbers of hematopoietic stem cells. Transplant of these cells in preclinical models resulted in enhanced, durable engraftment, in addition to highly immunosuppressive properties, leading to reduced GvHD.

Results from this study provide a robust dataset and proof of concept that MGTA-145, in combination with plerixafor, provides rapid and robust mobilization of stem cells and that these cells have better engraftment potential, are able to be gene modified and engraft and reduce GvHD in preclinical models compared to cells mobilized with other available agents. The data reinforce the availability of compelling opportunities for development in both the autologous and allogeneic transplant settings, said John Davis Jr., M.D., M.P.H., M.S., Head of Research & Development and Chief Medical Officer, Magenta Therapeutics.

The data were presented by Steven M. Devine, MD, Chief Medical Officer of the National Marrow Donor Program/Be The Match and Associate Scientific Director of the CIBMTR (Center for International Blood and Marrow Transplant Research).

Conditioning Program (MGTA-117 and CD45-ADC) Presentations at ASH

Magenta also provided updates on its conditioning platform at the ASH Annual Meeting, including MGTA-117 and CD45-ADC programs. Preclinical data from a study of MGTA-117 demonstrate that it is an effective, potent conditioning agent for transplant with anti-leukemic activity, significantly decreasing tumor burdens, leading to delayed tumor growth and increased median survival rates in animal models of AML. Ongoing GLP toxicology and GMP manufacturing progress continue to be supportive of advancing MGTA-117 towards an IND filing in AML and MDS.

Additionally, preclinical data from a study of Magentas CD45-ADC, a CD45-targeted conditioning agent designed to remove the cells that cause autoimmune diseases to enable curative immune reset, demonstrated the ability to achieve successful outcomes as a single agent in the most challenging disease model through fully mismatched allogeneic hematopoietic stem cell transplant, where only radiation or combinations of toxic chemotherapies are available, potentially providing patients the option of a reduced toxicity conditioning regimen. The company continues to evaluate this program preclinically.

About MGTA-145

MGTA-145 is being developed in combination with plerixafor to harness complementary chemokine mechanisms to mobilize hematopoietic stem cells for collection and transplantation. This new combination has the potential to be the preferred mobilization regimen for rapid and reliable mobilization and collection of hematopoietic stem cells to improve outcomes in autologous and allogeneic stem cell transplantation, which can rebuild a healthy immune system for patients with blood cancers, genetic diseases and autoimmune disorders.

MGTA-145 has the potential to replace the current standard of care for patients and allogeneic donors who currently rely on the use of granulocyte-colony stimulating factor (G-CSF) alone or in combination with plerixafor, which can take up to five days or longer to mobilize sufficient numbers of stem cells, often resulting in significant bone pain and other side effects.

About Magenta Therapeutics

Magenta Therapeutics is a clinical-stage biotechnology company developing medicines to bring the curative power of immune system reset through stem cell transplant to more patients with blood cancer, genetic diseases and autoimmune diseases. Magenta is combining leadership in stem cell biology and biotherapeutics development with clinical and regulatory expertise, a unique business model and broad networks in the stem cell transplant world to revolutionize immune reset for more patients.

Magenta is based in Cambridge, Mass. For more information, please visit http://www.magentatx.com.

Follow Magenta on Twitter: @magentatx.

Forward-Looking Statement

This press release may contain forward-looking statements and information within the meaning of The Private Securities Litigation Reform Act of 1995 and other federal securities laws. The use of words such as may, will, could, should, expects, intends, plans, anticipates, believes, estimates, predicts, projects, seeks, endeavor, potential, continue or the negative of such words or other similar expressions can be used to identify forward-looking statements. The express or implied forward-looking statements included in this press release are only predictions and are subject to a number of risks, uncertainties and assumptions, including, without limitation risks set forth under the caption Risk Factors in Magentas Annual Report on Form 10-K filed on March 3, 2020, as updated by Magentas most recent Quarterly Report on Form 10-Q and its other filings with the Securities and Exchange Commission. In light of these risks, uncertainties and assumptions, the forward-looking events and circumstances discussed in this press release may not occur and actual results could differ materially and adversely from those anticipated or implied in the forward-looking statements. You should not rely upon forward-looking statements as predictions of future events. Although Magenta believes that the expectations reflected in the forward-looking statements are reasonable, it cannot guarantee that the future results, levels of activity, performance or events and circumstances reflected in the forward-looking statements will be achieved or occur. Moreover, except as required by law, neither Magenta nor any other person assumes responsibility for the accuracy and completeness of the forward-looking statements included in this press release. Any forward-looking statement included in this press release speaks only as of the date on which it was made. We undertake no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events or otherwise, except as required by law.

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Magenta Therapeutics Announces Commencement of First Phase 2 Clinical Trial of MGTA-145 for Stem Cell Mobilization, Oral Presentation of MGTA-145...

Bone Marrow Stem Cells Comments Off on Magenta Therapeutics Announces Commencement of First Phase 2 Clinical Trial of MGTA-145 for Stem Cell Mobilization, Oral Presentation of MGTA-145… | December 13th, 2020

Flotetuzumab was found to demonstrate antileukemic activity in patients with primary induction failure (PIF) and early-relapse acute myeloid leukemia (ER-AML), and the treatment appears tolerable with infrequent neurologic adverse events, according to results from an updated analysis of an ongoing open-label phase 1/2 study (ClinicalTrials.gov Identifier: NCT02152956). The preliminary findings were presented by Ibrahim Aldoss, MD, of the Gehr Family Center for Leukemia Research at City of Hope in Duarte, California, at the virtual 62nd American Society of Hematology (ASH) Annual Meeting and Exposition.

CD123 is overexpressed on AML cells, including leukemia stem cells, as well as other hematological malignancies, said Dr Aldoss. Flotetuzumab is a humanized CD3 x CD123 bispecific T-cell engager that redirects T cells to kill tumor cells expressing CD123.

The open-label, single-arm, multicenter, phase 1/2 study previously identified the recommended phase 2 dosage of flotetuzumab as 500 ng/kg/d administered via continuous infusion in 28-day cycles following a step-up lead-in dose administered during cycle 1 in week 1 of treatment. The primary objective of the study was to assess safety and antileukemic activity of flotetuzumab in patients with PIF/ER-AML.

A total of 44 patients (PIF, n= 27; ER-AML, n=17) were included in the study. Median patient age was 63.5 years (range, 28.0-81.0), and most patient were men (70.5%). According to the European LeukemiaNet (ELN) 2017 risk stratification criteria, the majority of patients had nonfavorable risk (97.7%).

Evidence of antileukemic activity was documented in 59.1% of patients, with a median decrease of 81.0% in bone marrow blasts. Median time to first response was 1 cycle (range, 1-3).

The combined complete response rate (CR, <5% bone marrow blast) and CR with partial hematologic recovery (CRh) was 25.0% (PIF, 33.3%; ER-AML, 11.8%) and 31.8% when including CR with incomplete hematologic recovery (CRi). Among the 14 patients with CR/CRh/CRi, 8 patients subsequently underwent stem cell transplantation.

In addition, morphologic leukemia-free state was reported in 3 patients (PIF, n=1; ER-AML, n=2). Of the 10 patients with TP53 mutation, 5 were reported to have CRR/CRh/CRi, and 3 of those patients (60.0%) underwent stem cell transplantation.

For all patients who achieved CR/CRh/CRi, median duration of response was 8.13 months, and median overall survival was 10.7 months.

Cytokine release syndrome (CRS), the most frequently reported treatment-related adverse event, occurred in 100% of patients (n=44; all grade). One grade 3 CRS event occurred. Approximately half of CRS events (52%) occurred during step-up dosing in the first week of treatment, and the incidence of CRS progressively decreased over time.

Neurologic adverse events were reported as infrequent and of mild to moderate severity (all-grade headache, n=13; 29.5%). Neurologic treatment-related adverse events of grade 3 or more were confusional state (n=3) and dizziness (n=1).

Flotetuzumab demonstrated encouraging activity in patients with primary induction failure in early-relapse AML, a population with poor prognosis and high unmet medical need, Dr Aldoss concluded.

The study (ClinicalTrials.gov Identifier: NCT02152956) is currently enrolling patients.

Disclosure: Some authors have declared affiliations with or received funding from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.

Read more ofHematology Advisorscoverage of the ASH 2020 meeting by visiting theconference page.

Aldoss I, Uy G, Vey N, et al. Flotetuzumab as salvage therapy for primary induction failure and early relapse acute myeloid leukemia. Presented at: American Society of Hematology (ASH) 62nd Annual Meeting and Exposition; December 5-8, 2020. Abstract 331.

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Antileukemic Activity Seen With Flotetuzumab in Primary Induction Failure, Early-Relapse AML - Hematology Advisor

Bone Marrow Stem Cells Comments Off on Antileukemic Activity Seen With Flotetuzumab in Primary Induction Failure, Early-Relapse AML – Hematology Advisor | December 13th, 2020

The following article features coverage from the ASH 2020 virtual meeting. Click here to read more of Oncology Nurse Advisors conference coverage.

Patients who received venetoclax with azacytidine for the treatment of higher-risk myelodysplastic syndrome (HR-MDS) had high overall survival rates and clinically meaningful improvements of dyspnea and fatigue through 48 weeks. These findings were presented during the American Society of Hematology (ASH) 62nd Annual Meeting and Exposition.

Jacqueline S. Garcia, MD, coauthor of this study, explained the mechanism of this therapy. Apoptosis is normally under tight control by the interaction between pro-survival and pro-biotic proteins. In HR-MDS, myeloblasts overexpress BCL-2 and blasts are generally highly prone to pro-apoptotic proteins. Azacytidine indirectly decreases other apoptotic proteins, which sensitizes cells to venetoclax. Venetoclax is a BCL-2 inhibitor, which induces death. Thus, these drugs have the potential to irreversibly commit the cell to death.

Patients (N=78) with HR-MDS who were not candidates for intensive chemotherapy were recruited for this ongoing, open-label, dose-escalation, phase 1b study. Study participants received venetoclax 400 or 800 mg for 28 days followed by an escalating dose (100, 200, and 400 mg) for 14 days in a 28-day cycle with azacitidine 75 mg/m2 subcutaneously or intravenously administered on the first 7 days of each cycle. Participants were assessed for adverse events and efficacy.

Patient group was 75% men, median age 71 years (range, 26 to 85) and 56% had very high-risk disease.

Of the 31 patients with baseline marrow data, the most frequent mutations were located in tumor protein p53 (TP53; 35.5%), additional sex combs like 1 (ASXL1; 19.4%), and stromal antigen 2 (STAG2; 16.1%).

All participants experienced at least 1 adverse event during the study. The most commonly observed events were constipation (54%), nausea (55%), and neutropenia (83%). Adverse events grade 3 or higher were experienced by 96% of patients and included febrile neutropenia (49%) and thrombocytopenia (42%). Few infections were observed, likely due to the antibiotic prophylaxis.

At 30 days, the mortality rate was 1% and 1.3% experienced disease progression. A total of 16 patients received post-study transplants (bone marrow, 7 patients; stem cell, 9 patients).

The objective response rate was 79%; in which 39.7% entered into complete remission, 39.7% into marrow complete remission, and 14.1% had stable disease.

The median duration of response was 12.9 months (range, 12.1 to 16.8), and among those who achieved complete remission, the median duration of response after remission was 13.8 months (range, 6.5 to 20.9). The median time to complete remission was 2.6 months (range, 1.2 to 19.6).

Physical function through 48 weeks was generally maintained and fatigue, dyspnea, and global health quality of life were improved among patients who received 400 mg of venetoclax for 14 days.

This study was limited by its small sample size and short duration; however, this study was still on-going, and a phase 3 trial has begun.

These results indicated venetoclax with azacitidine was efficacious, allowing for maintenance of physical functioning for up to 48 weeks among patients with HR-MDS who were not candidates for intensive chemotherapy.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.

Reference

Garcia JS, Wei AH, Borate U, et al. Safety, efficacy, and patient-reported outcomes of venetoclax in combination with azacitidine for the treatment of patients with higher-risk myelodysplastic syndrome: a phase 1b study. Presented at: American Society of Hematology (ASH) 62nd Annual Meeting and Exposition; December 5-8, 2020. Abstr 656.

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Venetoclax/Azacitidine Combination Efficacious for the Treatment of Older Patients With Higher-Risk Myelodysplastic Syndrome - Oncology Nurse Advisor

Bone Marrow Stem Cells Comments Off on Venetoclax/Azacitidine Combination Efficacious for the Treatment of Older Patients With Higher-Risk Myelodysplastic Syndrome – Oncology Nurse Advisor | December 13th, 2020