Mesenchymal stromal cell-based therapy: Regulatory and translational aspects in gastroenterology

Table 2 Synopsis of published clinical studies using mesenchymal stromal cells in perianal fistulizing and/or refractory Crohn’s disease

Ref.	Study design	Patients	Disease duration and characteristics	Assessment and follow-up	Source of cells	Dose	Safety outcomes (terminology)	Key safety results
García-Olmo et al[84] (2005)	Phase 1	9 patients aged 32-46	Diagnosis of CD at least 5 years before, unresponsive to medical treatment and unsuccessfully treated by classic surgery at least twice	Weekly follow-up for the first 8 wk, then monthly follow-up up max 30 mo	Autologous ASC	3-30 × 106	Not specified	No immediate adverse reactions (e.g., anaphylaxis, allergic reactions) were observed in any of the cases studied
Garcia-Olmo et al[85] (2009)	Open-label, multicenter, phase 2	24 patients with mean age = 52 received ASC+fibrin glue	Complex perianal fistula (either of cryptoglandular origin or associated with CD). In patients with CD, immunomodulators were used continuously for at least six months and stable for more than eight weeks	Week 8, 16 and then at 3-mo interval up to 12 months	Autologous ASC	2-4 × 107	Incidence of adverse events and serious adverse events	11 adverse events (at week 8), of which two were SAEs, but unrelated to ASC administration. In the following phase, 9 adverse event (perianal sepsis), unrelated to ASC administration
Ciccocioppo et al[86] (2011)	Prospective study	12 patients aged 16-44 (two drop outs)	Patients with CD unresponsive to or unsuitable for all previous medical treatment including biological agents or unsuccessfully treated by surgery	3, 6 and 12 mo	Autologous BM-MSC	Median 20 × 106	Changes in vital signs and adverse reactions during the first 6 h after each cellular treatment, and during the following 12-month follow-up	No changes in vital signs and no adverse events were recorded during the procedure and up to the end of the 6-h observation time, or during the 12-mo follow-up period
Guadalajara et al[87] (2012)	Retrospective follow up of phase 2	24 patients with mean age = 42	Patients enrolled in previous phase 2 study receiving at least one ASC administration	8 wk, 1 yr	Autologous ASC	Not specified	Number of adverse events since the final visit of the phase II study (serious or not, severity, causality)	Ischiorectal abscess (patient treated with fibrin glue alone) and a perianal abscess (patient treated with ASCs plus fibrin glue), both toxicity grade I and unrelated to the study treatment. These events occurred at 13 and 21 mo after the original treatment, respectively
Herreros et al[88] (2012)	Multicenter randomized single-blind Phase 3 + observational	200 patients with mean age = 50	Cryptoglandular complex fistula-in-ano (without CD)	1, 4 and 12, 14 24, 26, 48 wk	Autologous ASC	2 × 107 (± fibrin glue)	Incidence of adverse events and SAEs	Approximately 85%-90% of patients experienced an adverse event, but most of these were nonserious. There were 17 different AEs reported in more than 5% of the cases. The most frequent AEs were proctalgia (43.7%), abscess drainage (22.4%), pain (13.7%), perianal abscess (13.1%), pyrexia (0.3%), swelling (6.6%), and pruritus (6.6%). There were no statistically significant differences within groups. There were 37 SAEs in 30 patients. All but 4 SAEs were unrelated to study treatment
Lee et al[89] (2013)	Open-label phase 2	43 patients with mean age = 26	Perianal fistulae with CD in patients not treated with infliximab within 3 mo prior to ASC	4, 6 and 8 wk, 10 mo	Autologous ASC	Depending on the fistula (mean from 15 to 19 × 107)	Systemic tolerance, adverse events and SAEs	Post-operative pain (60%), anal pain (19%) and anal bleeding (7%), unrelated to ASC administration. One hospitalization for vitamin B12 deficit; two grade 3/4 events (exacerbation of disease and peritonitis), unrelated to ASC administration
de la Portilla et al[90] (2013)	Open-label phase 1/2a	24 patients with mean age = 36	Diagnosis of CD at least 12 mo before, presence of persistent and active complex perianal fistula with less than three fistulous tracts and/or external opening, non-active luminal CD; no treatment with infliximab or any other anti-TNF agent in the previous 8 wk or tacrolimus or cyclosporine in the previous 4 wk	10, 12, 22, 24 wk	Allogeneic ASC	2 × 107 (up to 4 × 107 if no effect)	Incidence of treatment emergent adverse events	32 treatment-emergent adverse events during the study, the majority of which were of mild to moderate intensity. Five treatment-related AEs were reported: “anal abscess” (3 patients), “pyrexia” (1), and “uterine leiomyoma” (1). Only two SAEs: “pyrexia” and “perianal abscess”, considered to be possibly related to the study treatment and both patients were withdrawn from the study
Ciccocioppo et al[91] (2015)	5-year follow up of an open-label phase 2	8 patients with median age = 37	Refractory CD or inability to undergo standard therapies	12 mo until 5 yr	Autologous BM-MSC	Not specified	Systemic tolerance, adverse events and SAEs, as specified in the Medical Dictionary for Regulatory Activities terminology	23 adverse events, mainly consisting of abdominal pain, headache, anal inflammation, diarrhea, erythema, nausea, and fever. All AEs were consistent with exacerbation of the primary disease, but cholecystectomy due to the presence of gallstones. None was attributed to MSC therapy, and no evidence of tumor development or opportunistic infection
Cho et al[92] (2013)	Open-label, multicenter, dose-escalation phase 1	10 patients with mean age = 26	Perianal fistula associated with CD	Weeks 8, months 4,6 and 8	Autologous ASC	1, 2 and 4 × 107 to 40 × 107	Adverse events reported after injection with ASCs, serious adverse events during study period, and laboratory toxicity observed after injection with ASCs. (CTCAE version 3.0)	13 adverse events were reported in seven patients (70%). The adverse events, which were mild or moderate in severity, were not related to study drug. There were no grade 3 or 4 adverse events and no laboratory toxicity greater than grade 3 in this study. Adverse events reported in two or more patients included pain (n = 3) and diarrhea (n = 2). During the study period, two patients reported three SAEs of grade 2 (enterocolitis, seton application, and infliximab administration for new fistulas unrelated to the target fistula) requiring hospitalization
Cho et al[93] (2015)	Retrospective analysis of 1-year follow up phase 2	42 patients with mean age = 26	Average duration of CD of 58 mo	2 yr	Autologous ASC	Average 16.4 × 107	Systemic tolerance, adverse events, SAEs	53 adverse events were reported in 30 patients (73.2%), the most common being abdominal pain (17.1%); eczema and exacerbation of disease (9.8%) and anal inflammation, diarrhea, and fever (7.3%). None was related to MSC administration
Garcia-Olmo et al[62] (2015)	Observational	28-76	Recurrent perianal fistulae who previously undergone at least three surgical interventions	Week 8 and year 1	Autologous ASC	Not specified	Not specified	No adverse reactions or complications related to MSC administration
Molendijk et al[66] (2015)	Phase 2, double-blind, placebo-controlled, randomized study	> 18	Actively draining perianal fistulizing CD (diagnosis at least 3 months before enrollment) refractory to conventional therapies	6, 12, and 24 wk	Allogeneic BM-MSC	1, 3 and 9 × 107	Primary endpoint: incidence of serious adverse events at week 12. (CTCAE, version 3.0). Secondary end point: incidence of surgical intervention and infections at week 12 and 24	No infusion reactions; one patient 2 developed fever 6 h after surgery. One patient in each group developed a perianal abscess that required surgical drainage. Reported adverse events: n = 17 (group 1, n = 5), 9 (group 2, n = 5), 10 (group 3, n = 5), 14 (placebo, n = 5). One patient (1 × 107) developed an adenocarcinoma of the cecum with peritoneal carcinomatosis > 15 mo after the surgical intervention
Dhere et al[52] (2016)	Phase 1 safety trial	18-52	Established CD for at least 3 mo refractory to conventional therapies (lack of response to immunomodulators and/or biologics for at least 3 mo)	1, 5 and 9 wk after infusion	Autologous BM-MSC	2, 5 and 10 × 106	Changes in respiratory or cardiovascular parameters during the 1 h infusion and for 4 h after. Temperature, heart rate, mean arterial pressure and respiratory rate assessed at 15 min, 30 min, 1 h, 2 h, 3 h and 4 h	No patient developed significant infusion reaction. SAEs in 7 patients, of which 2 likely to be related to MSC administration: appendicitis (with appendectomy 9 d after infusion and complete colectomy for medically refractory CD after 120 d) and C. difficile colitis (30 d after infusion)
Panés et al[63] (2016)	Phase 3, randomized, placebo-controlled trial	107 patients, mean age = 39	Actively draining perianal fistulizing CD refractory to conventional therapies	24 wk after local injection	Allogeneic ASC	12 × 106	TEAEs (MedDRA version 17.0)	18 patients of the ASC treated group vs 30 of 107 in the placebo group developed treatment-related adverse events, (anal abscess and proctalgia)

SAEs: Serious adverse events; TEAEs: Treatments emergent adverse events; ASC: Adipose-derived stem cells; CD: Crohn’s disease; MSC: Mesenchymal stromal cells; BM-MSC: Bone Marrow derived mesenchymal stromal cells. CTCAE: Common Terminology Criteria for Adverse Events; MedDRA: Medical Dictionary for Regulatory Activities.