Discussion
toxicity, infections, GVHD
INS, SHORT STATURE, DISEASE, INFECTIONS, ADVERSE EFFECTS, REMISSION, INFUSION REACTION, GVHD
The key finding of this open-label phase I study is that treatment with autologous BM-MSCs of both children and adults affected by steroid-dependent, multi-relapsing INS is feasible, safe, and well tolerated. These results were obtained despite considerable logistical difficulties related to the COVID-19 pandemic, which determined some incompleteness of data. Moreover, over 12 months of observation after BM-MSC infusion, treatment remarkably delayed the onset of relapses and reduced their incidence, and at the same time substantially reduced the need for glucocorticoids to maintain remission in children, whereas it was definitely not effective in adults.In terms of safety, numerous studies assessing the use of autologous MSCs in a consistent number of patients have shown no adverse effects (Consistently with the above considerations, the infusions of autologous BM-MSCs were well tolerated by all treated patients, with no infusion reactions and no subsequent AEs that could be linked to the study intervention. Perhaps more surprisingly, the procedure of harvesting and BM-MSC infusions was deemed tolerable by all patients, with positive feedback in health-related quality of life questionnaires for most patients.Another interesting finding of the study was that treatment benefit was restricted to children, whereas no treatment effect was observed in adults. Our finding, however, should be interpreted with caution. For reasons linked to the greater rarity of the condition in young adults, and to the major impact of the COVID-19 pandemic on this study, our adult population consisted of 6 patients, which limited the study power. On the other hand, this clinical observation found a correlate in the immunomonitoring, which revealed that in children, treatment with BM-MSCs appeared to directly determine in vivo a significant transient decrease in total, mature, and memory B cells and an increase in total, memory, and activated memory Treg cells, despite the tapering of concomitant immunosuppression. In contrast, we failed to detect any appreciable immune cell modulation in adults. In a previous report, heterologous BM-MSCs were safe and therapeutically effective in patients with refractory GVHD (61 children and 31 adults), with a tendency to a better outcome in terms of response and survival in children compared with adults (Severe forms of steroid-dependent NS are burdened by substantial morbidity, mainly related to the need for prolonged courses of immunosuppressive agents to maintain stable remission, which despite intense treatment is not always achieved. A few patients therefore require, in addition to their maintenance immunosuppression for years, repeated cycles of high-dose oral glucocorticoids. This treatment leads to marked side effects in terms of short stature, reduced bone mineral density, and severe infections and has a major impact on quality of life in terms of repeated hospitalizations, ability to attend school, socialize, participate in sports for patients, and of prolonged care for their families. Compared with standard of care with oral and i.v. immunosuppressive medications, the use of autologous BM-MSCs has the major advantage of low, or nil, morbidity, and allows children receiving it to experience a significant, albeit transient, improvement in their disease relapses and intensity of immunosuppression. We did not observe a significant reduction in the burden of glucocorticoid side effects in this study. Most likely, this is due to the transient benefit of BM-MSC treatment, which was invariably followed within 12 months by disease relapse, with the consequent need for repeated courses of oral prednisone in all patients.To the best of our knowledge, only 1 study on the safety and efficacy of MSC treatment was performed in an INS setting (The main limitations of our phase I study are the small sample size and the single-arm, open-label design, as well as the use of the patient’s prestudy status as a reference for the assessment of efficacy of BM-MSC infusions. This study design is justified by the rarity and severity of the disease and by the type of intervention. Thus, at this stage, the complexity of the intervention was acceptable only for patients with severe disease who were orphans of any alternative rescue therapy. The study design was approved by the Italian regulatory agency (i.e., AIFA) and conforms to EU guidelines.A few patients failed to fully recover data due to the major logistical difficulties related to the COVID-19 pandemic that precluded a complete per-protocol patient follow-up. However, we obtained complete clinical and safety data in 9 of 10 children and 5 of 6 adult patients, suggesting a benefit of treatment in children and no appreciable effect in adults. These encouraging findings may provide the background for a prospective, randomized, controlled trial of autologous BM-MSCs even in pediatric patients with less severe disease.Despite the limitations of a small phase I study, our findings suggest that a single infusion cycle of autologous BM-MSCs is safe and transiently effective in children with severe steroid-dependent NS. The clinical efficacy of this treatment approach in children is also reflected by in vivo modifications in B and T cell subpopulation profiles, with a transient decrease in total, mature, and memory B cells and a transient increase in total, memory, and activated memory Treg cells. More importantly, it identifies 3–6 months as the time period in which the immunomodulatory effect of the BM-MSC infusions peaks and then wanes. At this time, a second infusion cycle could prolong immunomodulation and optimize the therapeutic efficacy of BM-MSC treatment. This approach, which is supported by the reassuring safety profile of BM-MSC treatment in this setting, may be implemented in a phase II/III study targeting children with severe forms of steroid-responsive NS burdened by substantial toxicity, in whom the cost of this treatment may be justified by its significant potential benefit.