Feasibility, Safety, and Tolerance of Mesenchymal Stem Cell Therapy for Obstructive Chronic Lung Allograft Dysfunction

Abstract

Feasibility, tolerance, and safety of intravenous infusions of allogeneic mesenchymal stem cell (MSC) therapy in lung transplant recipients with bronchiolitis obliterans syndrome (BOS) are not well established. MSCs were manufactured, cryopreserved, transported to our facility, thawed, and infused into nine recipients with moderate BOS (average drop in forced expiratory volume in 1 second was 56.8% ± 3.2% from post‐transplant peak) who were refractory to standard therapy and not candidates for retransplant. Cells were viable and sterile prior to infusion. Patients received a single infusion of either 1 (n = 3), 2 (n = 3), or 4 (n = 3) million MSCs per kg. Patients were medically evaluated before; during; and at 24 hours, 1 week, and 1 month after infusion for evidence of infusion‐related adverse events and tolerance of therapy. Vital signs, pulmonary function test results, Borg Dyspnea Index, and routine laboratory data were recorded. Vital signs and O2 saturation did not significantly change during or up to 2 hours after MSC infusion. There were no significant changes in gas exchange variables, pulmonary function test results, or laboratory values at 1, 7, and 30 days postinfusion compared with preinfusion values. Infusion of MSCs in patients with BOS was feasible, safe, and well tolerated and did not produce any significant adverse changes in clinical, functional, or laboratory variables during or up to 30 days after infusion. Manufacturing, transport, and administration of intravenous, allogeneic bone marrow‐derived MSCs in doses from 1 to 4 million MSCs per kg is safe in lung transplant recipients with BOS. Stem Cells Translational Medicine 2018;7:161–167

Cell-based therapy to reduce mortality from COVID-19: Systematic review and meta-analysis of human studies on acute respiratory distress syndrome

“…This safety profile is consistent with the experience of other human clinical trials involving MSC therapy. 33,[37][38][39][40][41][42][43] The potential efficacy of MSC therapy for ARDS in COVID- Findings from this study also suggest the impact of MSC therapy on important immunologic and inflammatory processes that lead to organ injury in COVID-19-infected patients. Cytokine release syndrome is a major underlying pathophysiological process in ARDS and was found to decrease with MSC therapy in seven of the studies analyzed.…”

“…These showed clear decreases in pro-inflammatory cytokines, including IL-1, IL-6, TNF-α, and CRP, and increased lymphocytes and IL-10 within 5 days of MSC therapy (Table 5), [20][21][22]24,25,28 which supported an immunomodulatory effect of the MSC therapy. clinical studies have demonstrated that MSC therapy is safe and has the potential to mitigate inflammatory and physiologic damage for a variety of conditions involving the central nervous, 32,33 cardiac, 34,35 renal, 36 gastrointestinal, [37][38][39] and respiratory 40,41 systems. Our analysis of the literature suggests similar results for MSC therapy for treating ARDS in COVID-19 patients.…”

Insights into the use of mesenchymal stem cells in COVID-19 mediated acute respiratory failure

“…Most of the data demonstrating the beneficial effects mediated by MSCs have been obtained from studies conducted in vitro and in vivo; however, in clinical settings the therapeutic efficacy of MSC-based therapy has not been readily demonstrated. Although multiple MSC-based clinical studies have been completed in the pulmonary space for conditions like chronic obstructive pulmonary disease (COPD), ARDS, emphysema and obstructive chronic lung allograft dysfunction 36,[86][87][88][89][90] , these studies are primarily Phase 1 trials which evaluate safety and feasibility. Data from these earlystage clinical trials demonstrate that administration of MSCs was safe and well-tolerated with no serious adverse events being reported.…”

Induction of lung-like cells from mouse embryonic stem cells by decellularized lung matrix

“…As for lung tissues, successful decellularization has been reported in small animals including mice and rats [34] , [35] , as well as in pigs and humans [36] , [37] . Furthermore, in transplantation experiments that used a variety of different types of implanted cells, such as ES cells, iPS cells [38] , primary or immortalized airway and alveolar cells [6] , and bone marrow-derived mesenchymal stem cells (MSCs) [39] , cellular remobilization in decellularized lungs was shown. In those studies, L-Mat samples were only considered as structures for cell mobilization and inhabitance, and not examined as an inducer of differentiation.…”