Bone marrow transplant with post‐transplant cyclophosphamide for recessive dystrophic epidermolysis bullosa expands the related donor pool and permits tolerance of nonhaematopoietic cellular grafts

Abstract

Summary Background Recessive dystrophic epidermolysis bullosa (RDEB) is a severe systemic genodermatosis lacking therapies beyond supportive care for its extensive, life‐limiting manifestations. Objectives To report the safety and preliminary responses of 10 patients with RDEB to bone marrow transplant (BMT) with post‐transplant cyclophosphamide (PTCy BMT) after reduced‐intensity conditioning with infusions of immunomodulatory donor‐derived mesenchymal stromal cells (median follow‐up 16 months). Methods BMT toxicities, donor blood and skin engraftment, skin biopsies, photographic and dynamic assessments of RDEB disease activity were obtained at intervals from pre‐BMT to 1 year post‐BMT. Results Related donors varied from haploidentical (n = 6) to human leucocyte antigen (HLA)‐matched (n = 3), with one HLA‐matched unrelated donor. Transplant complications included graft failure (n = 3; two pursued a second PTCy BMT), veno‐occlusive disease (n = 2), posterior reversible encephalopathy (n = 1) and chronic graft‐versus‐host disease (n = 1; this patient died). In the nine ultimately engrafted patients, median donor chimerism at 180 days after transplant was 100% in peripheral blood and 27% in skin. Skin biopsies showed stable (n = 7) to improved (n = 2) type VII collagen protein expression by immunofluorescence and gain of anchoring fibril components (n = 3) by transmission electron microscopy. Early signs of clinical response include trends toward reduced body surface area of blisters/erosions from a median of 49·5% to 27·5% at 100 days after BMT (P = 0·05), with parental measures indicating stable quality of life. Conclusions PTCy BMT in RDEB provides a means of attaining immunotolerance for future donor‐derived cellular grafts (ClinicalTrials.gov identifier NCT02582775). What's already known about this topic? Severe, generalized recessive dystrophic epidermolysis bullosa (RDEB) is marked by great morbidity and early death. No cure currently exists for RDEB. Bone marrow transplant (BMT) is the only described systemic therapy for RDEB. What does this study add? The first description of post‐transplant cyclophosphamide (PTCy) BMT for RDEB. PTCy was well tolerated and provided excellent graft‐versus‐host disease prophylaxis, replacing long courses of calcineurin inhibitors in patients receiving human leucocyte antigen‐matched sibling BMT. What is the translational message? The PTCy BMT platform permits identification of a suitable related donor for most patients and for subsequent adoptive transfer of donor nonhaematopoietic cells after establishment of immunological tolerance.

Epidermolysis Bullosa-Associated Squamous Cell Carcinoma: From Pathogenesis to Therapeutic Perspectives

“…As for other cells with stem functionality, human umbilical cord blood-derived unrestricted somatic stem cells (USSCs) have shown anti-fibrotic effects and amelioration of disease phenotype in col7a1 −/− mice through the up-regulation of two relevant TGF-β1 antagonists: DCN and TGF-β3 [110,111,112]. However, pilot cell therapy trials on RDEB patients revealed modest to absent clinical efficacy and improvement in patient’s quality of life, low-tolerability or severe side effects [113,114,115,116,117].…”

Current Advanced Therapies Based on Human Mesenchymal Stem Cells for Skin Diseases

“…In each clinical trial 10 patients received intravenous infusions of hBM-MSCs [2× 10 6 cells/kg to 4 × 10 6 cells/kg ( Rashidghamat et al, 2020 )]. In the case of Ebens et al two of the transplants provoked veno-occlusive disease of the liver and 1 of the patients developed graft versus host disease ( Ebens et al, 2019 ). After 1 year of follow-up, skin biopsies showed stable ( n = 7) to improved ( n = 2) type VII collagen protein expression and gain of anchoring fibril components ( n = 3) ( Ebens et al, 2019 ) and total blister count over the entire body surface area showed a decrease compared with baseline ( Rashidghamat et al, 2020 ).…”

Translational perspectives to treat Epidermolysis bullosa—Where do we stand?

“…[ 42 ] However, even with minimum intensity conditioning protocols, morbidity and mortality still remain high (10%‐15%). [ 43,44 ] Addition of mesenchymal stem cell (MSC) infusions is currently being evaluated for an immunosuppressive effect, potentially allowing for a further attenuated conditioning regimen and lower peri‐interventional risks of immunomyeloablation. [ 45,46 ] (NCT02582775, NCT01033552) Apart from enhancing the safety and efficacy of the HSCT, MSCs may also serve as an additional source of renewable cells for the treatment of focal areas of residual blistering.…”