Allogeneic Adipose Tissue-derived Mesenchymal Stromal Cells(APHP)

Systemic sclerosis (SSc) is a rare, severe and chronic systemic autoimmune disease (AD) characterized by vasculopathy, immune dysregulation and fibrosis leading to multi-organ dysfunction (primarily skin, lungs, heart gastrointestinal tract and kidneys), with high morbidity and mortality, altered health-related quality of life, all at high cost for patients and society.
Treatment are mostly symptomatic and only autologous hematopoietic stem cell transplantation (AHSCT) has shown long term improvement in overall and event-free survival with disease-modifying properties. However, AHSCT is contra-indicated in case of advanced visceral involvement and in eligible patients, it is still associated with risk of toxicity. There is an urgent need to identify safe and effective treatments for severe SSc.
Mesenchymal stromal cells (MSC) are multipotent cells which carry immunomodulatory, pro-angiogenic and anti-fibrotic properties, that can target SSc pathogenesis and its clinical manifestations. The increasing use of MSC, harvested from bone marrow (MSC(M)), adipose tissue (MSC(AT)), or umbilical cord (MSC(UC)) in a variety of indications, provides consistent evidence supporting their safety in humans. The efficacy of MSC(M) intravenous (IV) injection for treating acute graft versus host disease led to their marketing approval in 2012 and MSC(AT) (Alofisel) were approved for severe Crohn's fistula in 2018.
MSC represent a promising therapeutic approach for SSc. We have previously a) shown disease-specific abnormalities in MSC(M) from SSc patients, providing strong rationale to use allogeneic MSC to treat SSc patients, b) published the first phase I/II dose escalation trial using allogenic MSC(M) infusion in 20 severe SSc patients (ClinicalTrials.gov: NCT02213705, PHRC AOM 11-250) with no safety issues, significant improvement in skin fibrosis at 3 to 6 months after infusion which appeared lower thereafter, thereby supporting the need for repeated infusions.
In vitro, experimental and clinical studies suggest that MSC properties vary according to their tissue of origin/source. We demonstrated that compared to MSC(M), MSC(AT) are easier to harvest and display higher proliferative capability before entering senescence, higher genetic stability, and superior immunosuppressive properties.
Considering the above rationale, we hypothesize that use of healthy donors allogeneic MSC(AT) produced by Etablissement Français du Sang (EFS) will demonstrate a) no safety issues, b) an efficacy profile that will increase with repeated infusion of allogeneic MSC(AT) to treat SSc.