Long-term Evaluation of Allogeneic Bone Marrow-derived Mesenchymal Stromal Cell Therapy for Crohn’s Disease Perianal Fistulas

Abstract

Background and Aims The long-term safety and efficacy of allogeneic bone marrow-derived mesenchymal stromal cell [bmMSC] therapy in perianal Crohn’s disease [CD] fistulas is unknown. We aimed to provide a 4-year clinical evaluation of allogeneic bmMSC treatment of perianal CD fistulas. Methods A double-blind dose-finding study for local bmMSC therapy in 21 patients with refractory perianal fistulising Crohn’s disease was performed at the Leiden University Medical Center in 2012–2014. All patients treated with bmMSCs [1 x 107 bmMSCs cohort 1, n = 5; 3 × 107 bmMSCs cohort 2, n = 5; 9 × 107 bmMSCs cohort 3, n = 5] were invited for a 4-year evaluation. Clinical events were registered, fistula closure was evaluated, and anti-human leukocyte antigen [HLA] antibodies were assessed. Patients were also asked to undergo a pelvic magnetic resonance imaging [MRI] and rectoscopy. Results Thirteen out of 15 patients [87%] treated with bmMSCs were available for long-term follow-up. Two non-MSC related malignancies were observed. No serious adverse events thought to be related to bmMSC therapy were found. In cohort 2 [n = 4], all fistulas were closed 4 years after bmMSC therapy. In cohort 1 [n = 4] 63%, and in cohort 3 [n = 5] 43%, of the fistulas were closed, respectively. In none of the patients anti-HLA antibodies could be detected 24 weeks and 4 years after therapy. Pelvic MRI showed significantly smaller fistula tracts after 4 years. Conclusions Allogeneic bmMSC therapy for CD-associated perianal fistulas is also in the long-term a safe therapy. In bmMSC-treated patients, fistulas with closure at Week 24 were still closed after 4 years.

Hyaluronan Hydrogels for the Local Delivery of Mesenchymal Stromal Cells to the Injured Vocal Fold

“…ADSCs in HA hydrogel have also reported to significantly improve disc function in patients with chronic discogenic lower back pain (220). Similar positive findings have also been reported regarding the use of local administration for tissue repair responses, including the closure of fistulas in Crohn's disease patients with, as previously reported, no negative side effects of MSC treatment (221). Intramuscular injection of allogenic MSCs have also been safely employed for the treatment of digital ulcers in systemic sclerosis autoimmune disease(222).…”

“…MSCs have been shown in multiple organ systems to play a pivotal role in tissue homeostasis and repair (219)(220)(221)(222)(266)(267)(268)(269).Their ability to home to sites of injury and modulate the activity of both immune cells and resident stromal fibroblasts has established fundamental reparative roles for MSCs in all phases of the healing cascade (142,270,271).…”

Crohn’s Disease: Hematopoietic and Mesenchymal Stem Cell Therapy as Potential Treatment

“…The most success was found in cohort 2 as all fistulas were closed 4 years after bonemarrow MSC therapy was locally applied. Success was also found in cohort 1 and 3 as 63% and 43% of the fistulas were closed upon reevaluation [42]. A phase II pilot clinical study by Liang et al, treated 9 individuals suffering from CD with allogeneic BM-MSC transplantation.…”

Mesenchymal stromal cell therapies: immunomodulatory properties and clinical progress

“…In the early 1990s, Crohn's disease patients were reported to experience relief from their inflammatory bowel disease following infusion of HSCs, and subsequently, HSC transplantation has been developed for refractory patients that do not respond to conventional treatments involving steroids or immunosuppressive agents or anti-TNF therapy [166][167][168]. However, serious adverse effects accompanied HSC transplantation treatment [169][170][171][172], which triggered the attempts to employ allogeneic or autologous MSCs for Crohn's disease therapy. Early phase studies reported encouraging observations and autologous BM-MSC exhibited efficacy with improved Crohn's disease activity index scores [173][174][175][176].…”