Quality Control Optimization for Minimizing Security Risks Associated with Mesenchymal Stromal Cell-Based Product Development.

Mesenchymal stromal cells (MSCs) have been considered a therapeutic strategy in regenerative medicine because of their regenerative and immunomodulatory properties. The translation of MSC-based products has some challenges, such as regulatory and scientific issues. Quality control should be standardized and optimized to guarantee the reproducibility, safety, and efficacy of MSC-based products to be administered to patients. The aim of this study was to develop MSC-based products for use in clinical practice. Quality control assays include cell characterization, cell viability, immunogenicity, and cell differentiation; safety tests such as procoagulant tissue factor (TF), microbiological, mycoplasma, endotoxin, genomic stability, and tumorigenicity tests; and potency tests. The results confirm that the cells express MSC markers; an average cell viability of 96.9%; a low expression of HLA-DR and costimulatory molecules; differentiation potential; a high expression of TF/CD142; an absence of pathogenic microorganisms; negative endotoxins; an absence of chromosomal abnormalities; an absence of genotoxicity and tumorigenicity; and T-lymphocyte proliferation inhibition potential. This study shows the relevance of standardizing the manufacturing process and quality controls to reduce variability due to the heterogeneity between donors. The results might also be useful for the implementation and optimization of new analytical techniques and automated methods to improve safety, which are the major concerns related to MSC-based therapy.

Safety and long-term improvement of mesenchymal stromal cell infusion in critically COVID-19 patients: a randomized clinical trial.

BACKGROUND: COVID-19 is a multisystem disease that presents acute and persistent symptoms, the postacute sequelae (PASC). Long-term symptoms may be due to consequences from organ or tissue injury caused by SARS-CoV-2, associated clotting or inflammatory processes during acute COVID-19. Various strategies are being chosen by clinicians to prevent severe cases of COVID-19; however, a single treatment would not be efficient in treating such a complex disease. Mesenchymal stromal cells (MSCs) are known for their immunomodulatory properties and regeneration ability; therefore, they are a promising tool for treating disorders involving immune dysregulation and extensive tissue damage, as is the case with COVID-19. This study aimed to assess the safety and explore the long-term efficacy of three intravenous doses of UC-MSCs (umbilical cord MSCs) as an adjunctive therapy in the recovery and postacute sequelae reduction caused by COVID-19. To our knowledge, this is one of the few reports that presents the longest follow-up after MSC treatment in COVID-19 patients. METHODS: This was a phase I/II, prospective, single-center, randomized, double-blind, placebo-controlled clinical trial. Seventeen patients diagnosed with COVID-19 who require intensive care surveillance and invasive mechanical ventilation-critically ill patients-were included. The patient infusion was three doses of 5 × 105 cells/kg UC-MSCs, with a dosing interval of 48 h (n = 11) or placebo (n = 6). The evaluations consisted of a clinical assessment, viral load, laboratory testing, including blood count, serologic, biochemical, cell subpopulation, cytokines and CT scan. RESULTS: The results revealed that in the UC-MSC group, there was a reduction in the levels of ferritin, IL-6 and MCP1-CCL2 on the fourteen day. In the second month, a decrease in the levels of reactive C-protein, D-dimer and neutrophils and an increase in the numbers of TCD3, TCD4 and NK lymphocytes were observed. A decrease in extension of lung damage was observed at the fourth month. The improvement in all these parameters was maintained until the end of patient follow-up. CONCLUSIONS: UC-MSCs infusion is safe and can play an important role as an adjunctive therapy, both in the early stages, preventing severe complications and in the chronic phase with postacute sequelae reduction in critically ill COVID-19 patients. Trial registration Brazilian Registry of Clinical Trials (ReBEC), UTN code-U1111-1254-9819. Registered 31 October 2020-Retrospectively registered, https://ensaiosclinicos.gov.br/rg/RBR-3fz9yr.

Combined Use of Tocilizumab and Mesenchymal Stromal Cells in the Treatment of Severe Covid-19: Case Report.

The coronavirus pandemic is one of the most significant public health events in recent history. Currently, no specific treatment is available. Some drugs and cell-based therapy have been tested as alternatives to decrease the disease's symptoms, length of hospital stay, and mortality. We reported the case of a patient with a severe manifestation of COVID-19 in critical condition who did not respond to the standard procedures used, including six liters of O2 supplementation under a nasal catheter and treatment with dexamethasone and enoxaparin in prophylactic dose. The patient was treated with tocilizumab and an advanced therapy product based on umbilical cord-derived mesenchymal stromal cells (UC-MSC). The combination of tocilizumab and UC-MSC proved to be safe, with no adverse effects, and the results of this case report prove to be a promising alternative in the treatment of patients with severe acute respiratory syndrome due to SARS-CoV-2.