Safety and efficacy of autologous and metabolically fit bone marrow mesenchymal stromal cells (BM-MSC) in medically refractory crohn's disease (CD)

CD is a chronic auto-inflammatory disorder with devastating consequences including need for multiple intestinal resections. The most effective therapy, anti- TNF biologics, poses risks for serious infections and malignancies demands alternative approaches including MSCs. Thawed BM-MSCs deploy a heat shock response and impaired immune suppression in vitro. We hypothesized metabolically fit “fresh” autologous MSCs may improve their clinical potency, hence we performed FDA approved Phase I dose escalation clinical trial in 12 human subjects with CD (NCT01659762). The primary end point was safety and tolerability while efficacy was secondary endpoints. Ages (18-52) with a CD Activity Index (CDAI) of >220 were enrolled. Screening included normal pulmonary and renal function tests, CXR and negative TB, CMV tests. Autologous MSCs were isolated from iliac bone marrow aspirate and propagated for 2-3 weeks with fibrinogen depleted human platelet lysate. 12 subjects (n = 4 in each group) received a single MSC intravenous infusion of either 2x10∧6 cells/kg, 5x10∧6 cells/kg, or 10x10∧6 cells/kg. Cells were infused over one hour with monitoring. MSCs were analyzed for cell surface marker by FACS to confirm identity, their ability to upregulate expression of IDO by IFNγ stimulation and inhibition of third party PBMC proliferation in vitro. Results: No dose limiting toxicity was seen. Data was available on 11 as one lost to follow up. One underwent an appendectomy and another developed Clostridium difficile colitis within 30 days of infusion. 5/11 subjects showed clinical response defined by drop of 100 points in CDAI score. 2/11 showed improvement of CRP. The initial clinical improvement seen in responsive subjects was not sustained beyond 4 weeks during follow up. No correlation in response was seen with MSC dose. MSC phenotype, cytokine responsiveness, and PBMC proliferation blockade were not different between patients or from control BMMSCs derived from normal volunteers. Single infusion of fresh autologous BM-MSCs propagated ex vivo using a non-xenogeneic growth supplement was safe and feasible at doses of up to 10x10∧6 cells/kg in patients with CD. Shortterm responses in disease activity and CRP were lost within weeks. Future phase II study with multiple culture rescued and metabolically fit autologous BMMSC infusions at cell doses up to 10x10∧6 cells/kg per infusion would be required to test whether the incidence and duration of clinical response can be improved.