Mesenchymal stem cell treatment for IPF—time for phase 2 trials?

Idiopathic pulmonary fibrosis (IPF) is a specific form of interstitial lung disease characterised by progressive fibrotic changes of unknown cause. Despite advances in treatment with the approval of two anti-fibrotic drugs, IPF remains a lethal disease with poor prognosis requiring new treatment methods. Mesenchymal stem cells (MSCs) have been studied as potential therapeutic agents for lung diseases due to their tissue reparative and immunomodulatory properties. Promising data from animal studies have led to novel human trials assessing the safety of MSCs in patients with IPF. In the October issue of Chest, Glassberg and colleagues published the AETHER study, the second safety trial of allogeneic human MSCs treatment in patients with IPF. In this non-randomised, non-placebo single-centre clinical trial, bone marrow-derived MSCs from two men were cultured and subsequently administered as a single intravenous infusion to nine patients with mild to moderate IPF. No treatment-related serious adverse events were reported with infusions up to 2 × 108 cells over a 60-week follow-up period. Two non-study related deaths were recorded. Non-serious adverse events unrelated to treatment were reported in most patients (78%), most frequently bronchitis and common cold. Mean absolute declines of 3·0% in % predicted FVC and 5·4% in % predicted DLCO were described in the 60 weeks after infusion, which are below the internationally accepted thresholds representing disease progression. To our knowledge, this is the third completed phase 1b trial of MSC administration in IPF and the first in-man study with allogeneic bone marrow-derived MSCs. The safety of three types of MSCs have been successfully tested so far in IPF: autologous adipose tissue-derived stromal cells administered endobronchially, intravenous administration of placenta-derived MSCs, and bone marrow-derived MSCs. Despite the wealth of preclinical studies for the use of MSCs in pulmonary fibrosis models, human trials have been delayed following safety risks coupled to a limited knowledge of the mechanism of action of the various stem cell therapies that inevitably hinders the choice of optimal cell therapy. The risks of pulmonary embolism and inappropriate proliferation, differentiation, or homing of the systemically administered cells have been among the foremost concerns associated with stem cell therapies in IPF. Preclinical models have raised questions regarding the pro-fibrotic reprogramming of these cells in the lungs of patients with IPF that could worsen fibrosis due to differentiation to myofibroblasts and macrophages. However, both phase 1 studies of allogeneic healthy donor MSCs, either from placenta or bone marrow, showed only mild and self-limiting adverse effects following intravenous injection of MSCs. The patients were followed up from 6 months to 12 months, and in all trials lung diffusing capacity and 6MWT did not show disease worsening beyond the expected background rate, with respect to disease severity at the date of enrolment. Furthermore, although the numbers of the enrolled patients were low (31 patients), the rate of disease progression observed in all three studies was met with cautious optimism by the investigators of all phase 1b studies. Considerable reluctance to use the stem cell therapy has been caused by not knowing the exact mechanism of their action. These cells are currently thought to exert their effects through paracrine mediators including soluble factors and MSC-derived microvesicles carrying cellular components, including mitochondria, to the compromised cells. Several studies have shown that MSCs' secreted factors resolve inflammation, control immune cell proliferation and function, and have antioxidant properties. However, their precise action at the cellular and molecular level in IPF has only been examined in animals treated with bleomycin or other fibrosis mediators, and usually at early times following the administration of the injurious stimuli. Consequently, this has raised a major concern about the translation of these preclinical MSCs studies into successful clinical trials able to show therapeutic potential. Notably, although promising data are emerging from MSC-based clinical trials in acute respiratory distress syndrome, the likelihood of an effect from therapy for a chronic disease like IPF is uncertain. Furthermore, the possible interaction of the approved antifibrotic and antiproliferative IPF therapies with MSCs treatment should be explored. The AETHER trial results justify the safety of intravenous infusions of allogeneic bone marrow-derived human MSCs in IPF. Along with the two previous clinical trials, sufficient evidence supports the enrolment of larger patient numbers as well as further dosing studies and testing of different schedules with efficacy endpoints. Several unanswered questions remain including whether to use self or healthy donor cells, their source, and the stem cell potential or character that would be optimal for the treatment of IPF. Unless substantial work is undertaken to fully understand these issues, treatment regimens will remain highly imprecise, speculative, and will hamper the development of the full potential of these experimental therapies, or even worse, lead to possible failure of future efficacy trials. For the study by Glassberg and colleagues see Chest 2017; 151: 971–81 For the study by Glassberg and colleagues see Chest 2017; 151: 971–81 All authors declare no competing interests.