Clinical research overview

Graft versus host disease (GvHD) is the clinical condition in which bone marrow-derived mesenchymal stromal cells (MSCs) have been most frequently studied. The review summarizes clinical trial experiences. While MSC-based therapy has shown an exceptional safety profile, identifying potency assays and disease biomarkers that reliably predict the capacity of a specific MSC batch to alleviate GvHD has been difficult. The authors note that GvHD diagnosis relies solely on clinical criteria, potentially obscuring outcomes. Evidence indicates importance of considering not only the cell product but also patient-specific biomarkers and/or immune characteristics in determining MSC responsiveness. The recommended approach involves combined analysis of clinical outcomes and both biomarkers of disease activity and MSC potency assays.

Severe graft-versus-host disease (GVHD) is a life-threatening complication after allogeneic transplantation with haemopoietic stem cells. Mesenchymal stem cells modulate immune responses in vitro and in vivo. The study aimed to assess whether mesenchymal stem cells could ameliorate GVHD after haemopoietic-stem-cell transplantation.

Steroid-refractory chronic graft-vs-host disease (cGvHD) contributes to morbidity after allogeneic hematopoietic stem cell transplantation. The study reports 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 according to National Institutes of Health criteria accompanied by improvement in GvHD-related symptoms and quality of life. Responses were durable, with systemic immunosuppressive therapy withdrawn from two responders, and a further two free from steroids and tapering calcineurin inhibitors. Responders showed distinct immune phenotype characterized by higher levels of naïve T cells and B cells before treatment compared with the nonresponders. MSC treatment associated with significant increases in naïve T cells, B cells, and Tregs 7 days after each infusion. Skin biopsies showed resolution of epidermal pathology. The authors propose CXCL9 and CXCL10 as early biomarkers for responsiveness to MSC treatment.

Steroid-refractory acute graft-versus-host disease (SR-aGVHD) following hematopoietic cell transplantation (HSCT) is associated with poor clinical outcomes. The study notes there are no safe and effective therapies approved for use in the pediatric population under the age of 12 years. Early trials demonstrated efficacy in the treatment of acute GVHD (aGVHD) in pediatric patients. This phase 3 multicenter study (NCT02336230) involved 54 children with primary SR-aGVHD who were naive to other immunosuppressant therapies for aGVHD treated with MSC product (remestemcel-L) dosed at 2 × 106 cells/kg twice weekly for 4 weeks. Results showed Remestemcel-L therapy significantly improved day 28 overall response rate (OR) compared with the prespecified control OR value of 45% (70.4% versus 45%, P = .0003). The statistically significant response was sustained through day 100, including an increase in complete response from 29.6% at day 28 to 44.4% at day 100. Overall survival reached 74.1% at day 100 and 68.5% at day 180. Response at day 28 proved highly predictive of improved survival through 180 days, with survival significantly greater in day 28 responders compared with nonresponders through day 100 (86.8% versus 47.1%, P = .0001) and through day 180 (78.9% versus 43.8%, P = .003). The product was well tolerated with no identified infusion-related toxicities or other safety concerns. The study provides robust, prospective evidence of the safety, tolerability, and efficacy of remestemcel-L as first-line therapy.

Uncontrolled studies have suggested that bone marrow-derived mesenchymal stem cells (MSCs) may be effective against acute graft-versus-host disease (aGVHD). This multicenter randomized study assessed efficacy of using ex vivo cultured adult human MSC (remestemcel-L) in addition to second-line therapy to treat steroid-refractory aGVHD (NCT00366145). The study enrolled 260 patients, 6 months to 70 years of age from August 2006 to May 2009, randomized 2:1 to receive 8 intravenous infusions of remestemcel-L or placebo, given over 4 weeks, in addition to second-line therapy. Four additional infusions were indicated for incomplete responders at day 28. Efficacy assessment continued through 180 days, with primary endpoint being durable complete response (DCR), defined as complete resolution of aGVHD symptoms for any period of at least 28 days after beginning treatment. Overall, Remestemcel-L did not meet the primary endpoint of greater DCR in the intent-to-treat population (35% versus 30%; P = 0.42). Post hoc analyses revealed patients with liver involvement who received at least 1 infusion of remestemcel-L had a higher DCR, and higher overall complete or partial response rate (OR) than those who received placebo (29% versus 5%; P = .047). Among high-risk patients, remestemcel-L demonstrated significantly higher OR at day 28 than placebo (58% versus 37%; P = 0.03). Pediatric patients showed higher OR with MSCs compared with placebo (64% versus 23%; P = .05). Similar adverse event rates occurred between groups. Remestemcel-L was safe and well tolerated. Results of this study did not demonstrate superior DCR compared with placebo, though favorable clinical responses seen in some patient subsets may warrant further investigation.

Because of their well-described immunosuppressive properties, allogeneic adult human mesenchymal stromal cells (MSC) derived from bone marrow have demonstrated safety and efficacy in steroid refractory acute graft versus host disease (SR aGVHD). Clinical trials yielded variable success, and an optimal source of MSC has yet to be defined. The study notes importance of maternal-fetal interface immune tolerance, suggesting extraembryonic fetal tissues, such as the umbilical cord, may provide an superior tissue source of MSC to mediate immunomodulation in aGVHD.

Results showed Survival at 12 months post randomisation was 53% (n=8) in the MSC and 77% (n=10) in the control arm. Deaths in MSC-treated patients occurred due to relapse (n=1), and aGVHD (n=6). Control arm deaths resulted from relapse (n=1), aGVHD (n=1) and cGVHD (n=1). Time to death was similar in both arms, with median 93 days (range: 28–210) in MSC arm and 86 days (range: 46–295) in control arm. Authors note that use of 12-month overall survival as a primary endpoint is vulnerable to variations in treatment factors outside GVHD therapy.

Mesenchymal stem cells (MSCs) may be used to treat steroid-refractory graft versus host disease (GVHD). However, the effects of MSCs in haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) have not been confirmed in randomized studies.

Despite the curative potential of hematopoietic cell transplantation (HCT) for hematologic malignancies, graft-versus-host disease (GVHD) remains a substantial cause of morbidity and mortality, particularly if treatment is refractory. Additional immunosuppression often leads to opportunistic infections and organ dysfunction. Mesenchymal stromal cells are non-hematopoietic tolerogenic cells present in normal bone marrow (BM), which can be expanded ex vivo to therapeutic doses. The phase I single-center trial assessed MSC safety and early efficacy of an escalating number of doses (2 × 106/kg doses; dose level 1, single dose; dose level 2, two weekly doses; dose level 3, four weekly doses) in patients aged ≥12 years with treatment-refractory acute or chronic GVHD. Eleven patients enrolled received some or all planned infusions, with median age at enrollment of 37 years. The most common primary indication was leukemia, median time from HCT to first MSC infusion was 2.6 years. Infusions were well tolerated, with all severe adverse events expected and determined to be unlikely or definitely not related to the study. No dose-limiting toxicities occurred. For acute GVHD, three of four patients (or overlap with acute features) had responses seen at any timepoint, ranging from partial to complete. Chronic GVHD patients (n=7) showed overall response at 3 months was partial in five, stable in one, and progressive in one. No appreciable differences appeared between dose levels in lymphocyte subsets. The conclusion states autologous and culture-recovered MSCs were safe in the setting of refractory GVHD following HCT for hematologic malignancy, and clinical responses were most notable in patients with acute GVHD.

Cell therapy is a promising approach for the treatment of refractory ocular disease. This investigation examined efficacy of mesenchymal stromal cells (MSCs) for the treatment of dry eye associated with chronic graft-versus-host disease (cGVHD) and assessed the immunomodulatory effects of MSCs on regulatory CD8(+)CD28(-) T lymphocytes. A total of 22 patients with refractory dry eye secondary to cGVHD were enrolled. Results indicated symptoms of 12 out of 22 patients abated after MSCs transplantation by intravenous injection, improving in the dry eye scores, ocular surface disease index scores and the Schirmer test results. Clinical improvements were accompanied by increasing level of CD8(+)CD28(-) T cells, but not CD4(+)CD25(+) T cells, in the 12 patients who were treated effectively. These patients displayed significantly higher levels of Th1 cytokines (interleukin (IL)-2 and interferon-γ) and lower levels of Th2 cytokines (IL-10 and IL-4). In vitro, CD8(+) T cells were prone to differentiation into CD8(+)CD28(-) T cells after co-culture with MSCs. Conclusions state transfusion of MSCs improved the clinical symptoms in patients (54.55%) with refractory dry eye secondary to cGVHD. MSCs appear to exert their effects by triggering the generation of CD8(+)CD28(-) T cells.

Refractory acute graft-versus-host disease (aGVHD) is a major cause of death after allogeneic hematopoietic stem cell transplantation. This study evaluated the immunomodulation effects of mesenchymal stromal cells (MSCs) from bone marrow of a third-party donor for refractory aGVHD. The study included 47 patients with refractory aGVHD: 28 patients receiving MSC and 19 patients without MSC treatment. MSCs were administered at a median dose of 1 × 10(6) cells/kg weekly until patients got complete response or received 8 doses of MSCs. After 125 doses of MSCs were administered, with a median of 4 doses (range, 2 to 8) per patient, overall response rate was 75% in the MSC group compared with 42.1% in the non-MSC group (P = .023). No differences emerged in cytomegalovirus, Epstein-Barr virus infections, and tumor relapse between groups during aGVHD treatment and follow-up. The MSC group showed lower incidence and severity of chronic GVHD than controls (P = .045 and P = .005). Post-treatment measurements revealed higher ratio of CD3(+)CD4(+)/CD3(+)CD8(+) T cells, the frequencies of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs), and the levels of signal joint T cell-receptor excision DNA circles (sjTRECs) compared to pretreatment. MSC-treated patients showed higher Tregs frequencies and sjTRECs levels than those in the non-MSC group at 8 and 12 weeks. The conclusion indicates MSCs derived from bone marrow of a third-party donor are effective to refractory aGVHD. It might reduce the incidence and severity of chronic GVHD in aGVHD patients by improving thymic function and induction of Tregs but not increase the risks of infections and tumor relapse.

Despite the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT), the procedure is still associated with high toxicity in patients with refractory graft-versus-host disease (GvHD). Mesenchymal stromal cells (MSCs) are a new mode of therapy in the context of allo-HSCT. The study objective was to evaluate the safety and feasibility of the use of adipose tissue-derived MSCs (AT-MSCs) in patients with chronic GvHD.