Mesenchymal stem cell-derived exosomes for the treatment of acute rejection in pediatric and adult bowel transplant

Introduction: Mesenchymal stem cells (MSC) exert immunomodulatory effects mediated by cytokines, chemokines, growth factors and extracellular vesicles. MSC-derived exosomes, a subtype of extracellular vesicle, recapitulate the broad therapeutic effects of MSC without inducing an allogenic immune response and are relatively easy to generate at large scale. We describe the use of ExoFlo™, an MSC-derived exosome agent to treat refractory rejection in 2 patients following intestinal transplantation. Methods: ExoFlo was administered to two patients, one adult (age 47) and one child (age 7) under an emergency investigational new drug (eIND) authorized by the FDA. Both patients met histologic criteria for ongoing acute cellular rejection persistent after standard treatment. The pediatric patient received one cycle of ExoFlo, consisting of 3 doses each separated by 72 hours. The adult patient received four cycles (12 total doses). Each dose contained 15 mL of ExoFlo combined with 85 mL of normal saline and was administered intravenously over 60 minutes. Pre- and post-treatment enteroscopy was performed within a week of the start and end of treatment. On the day of treatment, baseline lab parameters were obtained and vital signs were monitored during and after infusion. Results: Both patients tolerated the infusions without any adverse effects. Post-treatment enteroscopy for the pediatric patient showed complete resolution of intestinal allograft ulcers and normal histopathology without evidence of inflammation or rejection (Figure 1). He underwent repeat enteroscopy on post-treatment day # 19 which showed superficial ulcers at the transplanted terminal ileum with histopathology showing focal increase in crypt apoptosis raising concerns for return of acute cellular rejection. The adult patient also showed complete resolution of intestinal allograft ulcers and normal histopathology without evidence of inflammation or rejection. She has not had return of graft dysfunction or rejection at 6 months post-treatment. Conclusion: We demonstrate that MSC-derived exosome therapy can be administered safely in a pediatric and an adult intestinal transplant recipient. Histologic resolution was achieved within days of exosome therapy and the degree of resolution was profound. Because of the lack of standard dosing of MSC exosomes, we are unable to draw conclusions about therapeutic durability from such a small cohort. MSC exosomes do confer a significant advantage over traditional immunosuppressive agents because of their safety and toxicity profile. There may be a role for MSC-derived exosomes in the treatment of acute intestine allograft rejection, especially in cases where traditional anti-rejection therapy has failed or is contraindicated.Figure 1a.: Deep ulcers of intestinal allograft one day prior to starting ExoFlo therapyFigure 1b.: One day post-treatment with ExoFlo