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AIMS CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy. METHODS AND RESULTS Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.6 ± 6.1% and scar size 19.4 ± 5.8%, in New York Heart Association class II or III. The proportion of major adverse cardiac events (MACE) was significantly decreased by CPCs alone (-22% vs. placebo, P = 0.043). Quality of life (Minnesota Living with Heart Failure Questionnaire score) was significantly improved by MSCs alone (P = 0.050) and MSCs + CPCs (P = 0.023) vs. placebo. Left ventricular ejection fraction, left ventricular volumes, scar size, 6-min walking distance, and peak oxygen consumption did not differ significantly among groups. CONCLUSIONS This is the first multicentre trial assessing CPCs and a combination of two cell types from different tissues in HF patients. The results show that treatment is safe and feasible. Even with maximal guideline-directed therapy, both CPCs and MSCs were associated with improved clinical outcomes (MACE and quality of life, respectively) in ischaemic HF without affecting left ventricular function or structure, suggesting possible systemic or paracrine cellular mechanisms. Combining MSCs with CPCs was associated with improvement in both these outcomes. These results suggest potential important beneficial effects of CPCs and MSCs and support further investigation in HF patients.

BackgroundThere is an ongoing critical need to improve therapeutic strategies for COVID-19 pneumonia, particularly in the most severely affected patients. Adult mesenchymal stem cell (MSC) infusions have the potential to benefit critically ill patients with acute respiratory syndrome SARS-COV-2 infection, but clinical data supporting efficacy are lacking.MethodsWe conducted a case-control study of critically ill patients with laboratory-confirmed COVID-19, severe acute respiratory distress syndrome (ARDS). To evaluate clinical responsiveness in the most critically ill patient we examined outcomes in a sub-group of those requiring extracorporeal membrane oxygenation (ECMO) support. Patients (n=9) were administered with up to 3 infusions of intravenous (IV) MSCs and compared to a local ECMO control group (n=31). The primary outcome was safety, and the secondary outcomes were all-cause mortality (or rate of hospital discharge), cytokine levels, and viral clearance.FindingsMSC infusions (12 patients) were well tolerated and no side effects occurred. Of ECMO patients receiving MSC infusions, 2 out of 9 died (22.2%; 95%CI: 2.8%, 60.0%) compared with a mortality of 15 of 31 (48.4%; 95%CI: 30.2%, 66.9%; p = 0.25) in the ECMO control group. Isolated plasma exosomes containing the SARS-COV-2 Spike protein decreased after MSC infusions between day 14 or 21 after administration (p=0.003 and p=0.005, respectively) and was associated with a decrease in COVID-19 IgG Spike protein titer at same time points (p = 0.006 and p=0.007, respectively). Control ECMO patients receiving convalescent plasma did not clear COVID-19 IgG over the same time frame.InterpretationTogether these findings suggest that MSC IV infusion is well tolerated in patients with a broad range of severity including the most severe COVID-19 ARDS requiring ECMO. These data also raise the possibility that MSCs, in addition to exerting an immunomodulatory effect, contribute to viral clearance and strongly support the conduct of randomized placebo-controlled trial.

// Samuel Golpanian 1,2 , Darcy L. DiFede 1 , Marietsy V. Pujol 1 , Maureen H. Lowery 3 , Silvina Levis-Dusseau 3,5 , Bradley J. Goldstein 1,7 , Ivonne H. Schulman 1,3,6 , Bangon Longsomboon 1 , Ariel Wolf 1 , Aisha Khan 1 , Alan W. Heldman 1,3,4 , Pascal J. Goldschmidt-Clermont 3,4 and Joshua M. Hare 1,3,4 1 Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA 2 Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA 3 Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA 4 Division of Cardiology, University of Miami Miller School of Medicine, Miami, FL, USA 5 Division of Endocrinology, University of Miami Miller School of Medicine, Miami, FL, USA 6 Division of Nephrology, University of Miami Miller School of Medicine, Miami, FL, USA 7 Department of Otolaringology, University of Miami Miller School of Medicine, Miami, FL, USA Correspondence to: Joshua M. Hare, email: // Keywords : aging, frailty, mesenchymal stem cells, allogeneic, Gerotarget Received : December 20, 2015 Accepted : January 30, 2016 Published : February 25, 2016 Abstract Frailty is a syndrome associated with reduced physiological reserves that increases an individual’s vulnerability for developing increased morbidity and/or mortality. While most clinical trials have focused on exercise, nutrition, pharmacologic agents, or a multifactorial approach for the prevention and attenuation of frailty, none have studied the use of cell-based therapies. We hypothesize that the application of allogeneic human mesenchymal stem cells (allo-hMSCs) as a therapeutic agent for individuals with frailty is safe and efficacious. The CRATUS trial comprises an initial non-blinded phase I study, followed by a blinded, randomized phase I/II study (with an optional follow-up phase) that will address the safety and pre-specified beneficial effects in patients with the aging frailty syndrome. In the initial phase I protocol, allo-hMSCs will be administered in escalating doses via peripheral intravenous infusion (n=15) to patients allocated to three treatment groups: Group 1 (n=5, 20 million allo-hMSCs), Group 2 (n=5, 100 million allo-hMSCs), and Group 3 (n=5, 200 million allo-hMSCs). Subsequently, in the randomized phase, allo-hMSCs or matched placebo will be administered to patients (n=30) randomly allocated in a 1:1:1 ratio to one of two doses of MSCs versus placebo: Group A (n=10, 100 million allo-hMSCs), Group B (n=10, 200 million allo-hMSCs), and Group C (n=10, placebo). Primary and secondary objectives are, respectively, to demonstrate the safety and efficacy of allo-hMSCs administered in frail older individuals. This study will determine the safety of intravenous infusion of stem cells and compare phenotypic outcomes in patients with aging frailty.

Background & Aim Manufacturing process validation of products used in clinical investigation is the regulatory requirement. Production must be prospectively validated to confirm the suitability of the product intended use. The validated process and data are crucial for the Chemistry, Manufacturing and Control (CMC) section of the Investigation of New Drug submission. Effective validation is expected to be designed to include all key components that defines product manufacturing consistency, reliability, product quality, and data accuracy. Methods, Results & Conclusion The key components in designing a validation should base on scientific knowledge, literature review and data obtained from the pre-clinical studies. The objective of the validation must be clearly defined to enable an effective process validation plan. It should include established measurable product quality indicators such as process parameters, in process QC (e.g. time points and sample sizes) and target product profile (acceptable product outcomes). Standard operating procedure must be developed to outline process to be followed throughout the manufacturing and testing processes. All raw materials including starting biological material specifications must also be established. Critical equipment used must be properly qualified. Tests and assay to be conducted must be validated. The validation should be conducted up to the preparation process of final product intended use. When starting raw material in manufacturing process is biological product, donor quality becomes the significant variable factor, plan should consider minimizing the variability by using repeated donor in multiple processes when possible. Unanticipated outcomes or worst case scenario, when occur, should be carefully documented and analyzed to determine probable causes and resolutions. Repetition of the process is necessary and should base on the analysis of process and data from the preceding validation processes. Raw data must always be included with validation results. Conclusion The biological product manufacturing process is complex; the extent of the validation should factor in all elements of product quality attributes and the intended use of the final product. Effective manufacturing process validation should be designed not only to ensure the manufacturing process consistency and reliability but also the highest degree of product quality and integrity of data.