A Phase IB/IIA Study of Remestemcel-L, an ex Vivo Culture-expanded Adult Allogeneic Bone Marrow Derived Mesenchymal Stem Cell Product, for the Treatment of Medically Refractory Ulcerative Colitis

The purpose of this study is to determine the safety and efficacy of using remestemcel-L, an ex vivo culture-expanded adult allogeneic bone marrow derived mesenchymal stem cell product (MSCs) delivered by targeted endoscopic delivery to treat people for medically refractory ulcerative colitis.
This study will enroll adult patients with medically refractory ulcerative colitis who are planning to switch biologic therapy or undergo colectomy as the next stage in their treatment plan.

开始日期2020-11-10

申办/合作机构

The Cleveland Clinic Foundation

[+1]

NCT04548583 / Unknown status临床1/2期IIT

A Phase IB/IIA Study of Remestemcel-L, an Ex-vivo Culture-expanded Adult Allogeneic Bone Marrow Derived Mesenchymal Stem Cell Product for the Treatment of Medically Refractory Crohn's Colitis

Crohn's disease has several phenotypes (inflammatory, stricturing, fistulizing) and location (small bowel, ileocecal, colon, and perianal). Approximately one third of patients have inflammation limited to the colon. Up to two thirds will become medically refractory and require a total abdominal colectomy for symptom control. The purpose of this study is to determine the safety and efficacy of using allogeneic bone marrow derived mesenchymal stem cells (MSCs) delivered by targeted endoscopic delivery to treat people for medically refractory Crohn's colitis.

开始日期2020-11-04

申办/合作机构

The Cleveland Clinic Foundation

[+1]

NCT04371393 / Terminated临床3期IIT

Mesenchymal Stromal Cells for the Treatment of Moderate to Severe COVID-19 Acute Respiratory Distress Syndrome

The mortality rate in SARS-CoV-2-related severe ARDS is high despite treatment with antivirals, glucocorticoids, immunoglobulins, and ventilation. Preclinical and clinical evidence indicate that MSCs migrate to the lung and respond to the pro-inflammatory lung environment by releasing anti-inflammatory factors reducing the proliferation of pro-inflammatory cytokines while modulating regulatory T cells and macrophages to promote resolution of inflammation. Therefore, MSCs may have the potential to increase survival in management of COVID-19 induced ARDS.
The primary objective of this phase 3 trial is to evaluate the efficacy and safety of the addition of the mesenchymal stromal cell (MSC) remestemcel-L plus standard of care compared to placebo plus standard of care in patients with acute respiratory distress syndrome (ARDS) due to SARS-CoV-2. The secondary objective is to assess the impact of MSCs on inflammatory biomarkers.

开始日期2020-04-30

申办/合作机构

Icahn School of Medicine at Mount Sinai

[+2]

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项与 Mesoblast, Inc. 相关的文献（医药）

2023-12-01·JTCVS open

Prospective randomized controlled trial of the safety and feasibility of a novel mesenchymal precursor cell therapy in hypoplastic left heart syndrome

Article

作者: Wittenberg, Rachel E ; Marx, Gerald R ; Leighton, Jonah ; Borow, Kenneth M ; Gauvreau, Kimberlee ; Moleon-Shea, Melinda ; Emani, Sitaram M

Objective:

To assess the safety and feasibility of low-dose, novel, allogenic mesenchymal precursor cell (MPC) therapy as an adjunct to left ventricular (LV) recruitment for patients with hypoplastic left heart syndrome (HLHS) and borderline left ventricles. MPC injections into the hypoplastic left ventricle may stimulate neovascularization and beneficial LV remodeling and may improve the likelihood of achieving biventricular (BiV) or 1.5 ventricle (1.5V) circulation.

Methods:

Children <5 years with prior single ventricle palliation undergoing LV recruitment surgery at a single center were randomized to MPC injections into the LV endocardium/papillary muscles (MPCs) or standard-of-care (controls) and followed for 24 months. The primary endpoint was safety, including (serious) adverse events (S/AEs), and panel reactive antibodies (PRAs). Secondary endpoints included BiV/1.5V conversion and LV size and function.

Results:

Nineteen subjects were enrolled, including 9 MPC recipients and 10 controls. Fourteen patients (74%) had >1 AE, and 2 patients had SAEs, both deemed unrelated to the trial product. AE severity and frequency were similar in the 2 groups. Baseline PRA levels were high, with no difference between the groups at 12 months. The overall probability of BiV/1.5V conversion was 0.16 (95% confidence interval [CI], 0.05 to 0.41) at 12 months and 0.52 (95% CI, 0.31 to 0.77) at 24 months. For patients with imaging data at both time points, increases in LV volumes from baseline to 12 months were larger in the MPC group by 3-dimensional echocardiography and cardiac magnetic resonance imaging. For children who successfully underwent BiV conversion (n = 12), full BiV conversion was achieved at 24 months in 5 of 5 (100%) MPC-treated children compared with 4 of 7 (57%) controls.

Conclusions:

MPC injections were considered safe and feasible in HLHS patients. More than 50% of subjects underwent BiV/1.5V conversion within 2 years. Larger trials are needed to investigate the therapeutic potential of MPCs in this population.

2023-02-01·American journal of respiratory and critical care medicine

A Randomized Trial of Mesenchymal Stromal Cells for Moderate to Severe Acute Respiratory Distress Syndrome from COVID-19

Article

作者: Duggal, Abhijit ; Marks, Mary E. ; Leshnower, Bradley G. ; Gelijns, Annetine C. ; Grossman, Fred ; Fernandes, Eustace ; Bagiella, Emilia ; Pagani, Francis D. ; Romero, Christian ; Iribarne, Alexander ; Parnia, Sam ; Bowdish, Michael E. ; Patel, Nirav C. ; Desai, Nimesh D. ; Moquete, Ellen G. ; Itescu, Silviu ; Vekstein, Andrew M. ; Hayes, Jack ; Rassias, Athos J. ; Moskowitz, Alan J. ; O’Sullivan, Karen ; Smith, Peter K. ; Osman, Keren ; Mack, Michael J. ; Williams, Judson B. ; Overbey, Jessica R. ; Gottlieb, Robert L. ; Golob, Jonathan L. ; Possemato, Tammie ; Hupf, Jonathan ; Burke, Elizabeth ; Hou, Peter C. ; Gillinov, Marc ; O’Gara, Patrick T. ; Chang, Helena L. ; Barkauskas, Christina E. ; Hollister, Beth A.

Rationale: There are limited therapeutic options for patients with coronavirus disease (COVID-19)-related acute respiratory distress syndrome with inflammation-mediated lung injury. Mesenchymal stromal cells offer promise as immunomodulatory agents. Objectives: Evaluation of efficacy and safety of allogeneic mesenchymal cells in mechanically-ventilated patients with moderate or severe COVID-19-induced respiratory failure. Methods: Patients were randomized to two infusions of 2 million cells/kg or sham infusions, in addition to the standard of care. We hypothesized that cell therapy would be superior to sham control for the primary endpoint of 30-day mortality. The key secondary endpoint was ventilator-free survival within 60 days, accounting for deaths and withdrawals in a ranked analysis. Measurements and Main Results: At the third interim analysis, the data and safety monitoring board recommended that the trial halt enrollment as the prespecified mortality reduction from 40% to 23% was unlikely to be achieved (n = 222 out of planned 300). Thirty-day mortality was 37.5% (42/112) in cell recipients versus 42.7% (47/110) in control patients (relative risk [RR], 0.88; 95% confidence interval, 0.64-1.21; P = 0.43). There were no significant differences in days alive off ventilation within 60 days (median rank, 117.3 [interquartile range, 60.0-169.5] in cell patients and 102.0 [interquartile range, 54.0-162.5] in control subjects; higher is better). Resolution or improvement of acute respiratory distress syndrome at 30 days was observed in 51/104 (49.0%) cell recipients and 46/106 (43.4%) control patients (odds ratio, 1.36; 95% confidence interval, 0.57-3.21). There were no infusion-related toxicities and overall serious adverse events over 30 days were similar. Conclusions: Mesenchymal cells, while safe, did not improve 30-day survival or 60-day ventilator-free days in patients with moderate and/or severe COVID-19-related acute respiratory distress syndrome.

2021-12-01·Respiratory research2区 · 医学

Effect of mesenchymal stromal cell infusions on lung function in COPD patients with high CRP levels

2区 · 医学

ArticleOA

作者: Weiss, Daniel J ; Tashkin, Donald ; Hayes, Jack ; Segal, Karen ; Casaburi, Richard

Abstract:

Background:

We previously reported a Phase 1/2 randomized placebo-controlled trial of systemic administration of bone marrow-derived allogeneic MSCs (remestemcel-L) in COPD. While safety profile was good, no functional efficacy was observed. However, in view of growing recognition of effects of inflammatory environments on MSC actions we conducted a post-hoc analysis with stratification by baseline levels of a circulating inflammatory marker, C-reactive protein (CRP) to determine the effects of MSC administration in COPD patients with varying circulating CRP levels.

Methods:

Time course of lung function, exercise performance, patient reported responses, and exacerbation frequency following four monthly infusions of remestemcel-L vs. placebo were re-assessed in subgroups based on baseline circulating CRP levels.

Results:

In COPD patients with baseline CRP ≥ 4 mg/L, compared to COPD patients receiving placebo (N = 17), those treated with remestemcel-L (N = 12), demonstrated significant improvements from baseline in forced expiratory volume in one second, forced vital capacity, and six minute walk distance at 120 days with treatment differences evident as early as 10 days after the first infusion. Significant although smaller benefits were also detected in those with CRP levels ≥ 2 or ≥ 3 mg/L. These improvements persisted variably over the 2-year observational period. No significant benefits were observed in patient reported responses or number of COPD exacerbations between treatment groups.

Conclusion:

In an inflammatory environment, defined by elevated circulating CRP, remestemcel-L administration yielded at least transient meaningful pulmonary and functional improvements. These findings warrant further investigation of potential MSC-based therapies in COPD and other inflammatory pulmonary diseases.Trial registration: Clinicaltrials.gov NCT00683722.

项与 Mesoblast, Inc. 相关的新闻（医药）

2023-02-27

·Science Daily

Novel heart failure treatment using cell therapy

Physician-scientists announced today the results of the largest cell therapy trial to date in patients with chronic heart failure due to low ejection fraction. The therapy benefited patients by improving the heart's pumping ability, as measured by ejection fraction, and reducing the risk of heart attack or stroke, especially in patients who have high levels of inflammation. Also, a strong signal was found in the reduction of cardiovascular death in patients treated with cells. Physician-scientists at The Texas Heart Institute announced today the results of the largest cell therapy trial to date in patients with chronic heart failure due to low ejection fraction. The therapy benefited patients by improving the heart's pumping ability, as measured by ejection fraction, and reducing the risk of heart attack or stroke, especially in patients who have high levels of inflammation. Also, a strong signal was found in the reduction of cardiovascular death in patients treated with cells. The findings are published in the Journal of the American College of Cardiology. Investigators in this landmark clinical trial have shown that a special immunomodulatory cell-type called MPC (mesenchymal precursor cells) developed by Mesoblast Inc., has the potential for the first time to address a major contributor to heart failure -- inflammation. Patients in the trial were on full guideline-recommended drug therapy for heart failure, suggesting that the effect of the cell therapy was synergistic with and additive to state-of-the-art heart failure medications. More than 6 million Americans have chronic heart failure, a progressive disease that leads to a weakening of the heart muscle and a loss of its pumping function. Most heart failure drugs used today are aimed at addressing the detrimental changes that occur in the heart as a result of complex neurohormonal pathways that are activated during heart failure to compensate for poor heart function. These activated pathways eventually contribute to the progression of heart failure and repeated hospitalizations. Despite advances in therapies targeting these pathways, mortality rates remain high. The unique mechanism of action of MPC appears to provide an alternative approach that has the potential to make a significant impact on the high mortality of this disease. DREAM-HF (Double-Blind Randomized Assessment of Clinical Events With Allogeneic Mesenchymal Precursor Cells in Heart Failure), sponsored by Mesoblast, was a phase 3 trial performed at 51 sites in 565 patients with chronic heart failure, who were also on standard-of-care heart failure treatment. The study, which had a mean follow-up of 30 months, was designed to examine the effects of MPC comprising immunoselected, culture-expanded mesenchymal precursor cells (MPCs), on the number of hospitalizations and major adverse cardiovascular events in heart failure. MPCs are a good candidate for use in heart failure with low ejection fraction because they have potent anti-inflammatory, pro-angiogenic, and pro-healing effects. The cells were obtained from the bone marrow of healthy adult donors. Cell-treated patients in the study received direct cardiac injections of MPCs, and control patients underwent a "sham" or mock procedure with no injections. MPC-treated patients showed significant strengthening of the left ventricular muscle within the first 12-months as measured by an increase in left ventricular ejection fraction, which measures the heart's pumping ability and is one of the metrics used to assess overall heart function. Over a mean follow-up of 30-months, treatment with MPCs reduced the risk of cardiovascular death, heart attack, or stroke, with a greater decrease in patients with increased inflammation. MPC treatment reduced the rate of heart attack or stroke by 58%, and the benefit rose to 75% in patients who had high levels of a blood marker for inflammation. Similarly to what was seen with these major adverse cardiovascular events, improvement in ejection fraction was even more pronounced in patients with higher inflammation levels. MPC therapy did not further reduce recurrent heart failure events requiring hospitalization over and above the effects of traditional drugs which reduce circulating volume overload caused by the maladaptive effects of neurohormonal activation. This aspect of heart failure treatment is already addressed by the currently available medications. "The results of DREAM-HF are an important step in understanding how cell therapy provides benefits in patients with chronic heart failure due to poor pump function. The cells appear to work by reducing inflammation, increasing microvascular flow, and strengthening heart muscle. Locally, in the heart, the MPCs can protect cardiac muscle cells from dying and can improve blood flow and energetics. In large blood vessels throughout the body, the reduced inflammation resulting from the activation of MPCs may decrease plaque instability, which is what leads to heart attacks and strokes. The cells seem to have a systemic immune modulatory and anti-inflammatory effect," according to the study's lead author, Dr. Emerson C. Perin, MD, PhD, FACC, Medical Director at The Texas Heart Institute. The DREAM-HF findings of long-term improvements in outcomes for patients with chronic heart failure due to low ejection fraction and poor pump function are an important milestone in the field of cell therapy for cardiovascular disease. The results help in identifying those heart failure patients with inflammation who are at greatest risk and most likely to benefit from MPC therapy and findings will be confirmed in future studies. This seminal trial sets the stage for eventually adding cell therapy to the treatment arsenal for heart failure. "The Texas Heart Institute has spent two decades pioneering the development of cellular therapies for the heart and continues to lead the world in this breakthrough work. For millions of people in the United States over the age of 20 who suffer from heart failure, MPC therapy could change the future of cardiovascular care for patients with heart failure due to inflammation," according to Dr. Joseph G. Rogers, CEO and President of The Texas Heart Institute and advanced heart failure specialist.

临床结果细胞疗法临床3期AHA会议

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