Treatment of chronic GvHD with mesenchymal stromal cells induces durable responses: A phase II study

Abstract

Steroid-refractory chronic graft-vs-host disease (cGvHD) contributes to morbidity after allogeneic hematopoietic stem cell transplantation. Here, we report on 11 patients with severe, refractory cGvHD treated with repeated infusions of allogeneic bone marrow-derived mesenchymal stromal cells (MSC) over a 6-to 12-month period. Six patients responded to MSC treatment following National Institutes of Health response criteria, accompanied by improvement in GvHD-related symptoms and quality of life. This response was durable, with systemic immunosuppressive therapy withdrawn from two responders, and a further two free from steroids and tapering calcineurin inhibitors. All responders displayed a distinct immune phenotype characterized by higher levels of naïve T cells and B cells before treatment compared with the nonresponders, and a significantly higher fraction of CD31+ naïve CD4+ T cells. MSC treatment was associated with significant increases in naïve T cells, B cells, and Tregs 7 days after each infusion. Skin biopsies showed resolution of epidermal pathology. CXCL9 and CXCL10 showed differential responses in responder and nonresponder patients. Our data support the use of MSC infusions as treatment for steroid-refractory cGvHD with durable responses. We propose CXCL9 and CXCL10 as early biomarkers for responsiveness to MSC treatment. Our results highlight the importance of the MSC recipient immune phenotype in promoting treatment response. This trial was registered at www.ClinicalTrials.gov as #NCT01522716.

Reiterative infusions of MSCs improve pediatric osteogenesis imperfecta eliciting a pro‐osteogenic paracrine response: TERCELOI clinical trial

“…In conclusion, and taking into account the limited number of patients, we can infer from the TERCELOI results that repeated MSCs therapy in pediatric patients is feasible and safe, supporting recent cell therapy attempts to other disorders based on sequential cell infusion. [61][62][63] Regarding the effectiveness and mode of action of MSCs therapy, clinical improvements and noticeable pro-osteogenic systemic response were detected as soon as the OI patients received the first cell infusion. Moreover, the clinical benefits persisted throughout the whole cell therapy treatment and up to the 2-year follow-up visit.…”

Phase I clinical trial of intra-bone marrow cotransplantation of mesenchymal stem cells in cord blood transplantation

“…Diagnosis, n (%) Neutrophils ≥0.5 × 10 9 /L 21 (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) 22 (20)(21)(22)(23)(24)(25) .85…”

“…19,22 These immunomodulatory effects of MSCs have already been clinically applied in the treatment of GVHD after allogeneic hematopoietic cell transplantation (HCT). [23][24][25][26][27] MSCs express a low level of HLA class I and are negative for HLA class II and costimulatory molecules such as CD80, CD86, and CD40, and, therefore, they are able to evade allogeneic rejection. 28,29 Furthermore, culture expansion of MSCs is relatively easy, and they can be stored by cryopreservation.…”

Hydrogen in Patients With Corticosteroid-Refractory/Dependent Chronic Graft-Versus-Host-Disease: A Single-Arm, Multicenter, Open-Label, Phase 2 Trial

“…Although the long-term outcome is not a primary endpoint of the study, our research indicates that the 4-year projected overall survival rate of 74.7% is encouraging. Recently, the number of studies on chronic GVHD have gradually increased ( 19 , 25 , 29 , 30 ), but few publications report the long-term survival rate of corticosteroid-refractory/dependent cGVHD. In a newly diagnosed children study, the 3-year survival rate is approximately 70% ( 31 ).…”