One more chance of fistula healing in inflammatory bowel disease: Stem cell therapy

Table 1 Composite of autologous adipose tissue derived stem cell therapy trials

Author	Yerr of study	Fistula site	Type of study	Study population	Method of administration	Healing type of fistula	Safety	Outcome
García-Olmo et al[5]	2003	RV	Case Report	1	Injection of cells into rectal mucosa	Fully healed	No AE or SAE	Complete resolution at 1 wk with closure still at 3 mo
Lee et al[6]	2013	TS SS IS ES	Clinical Trial, Phase II Multi-center	33	Fistula tract was curetted and irrigated and then ASCs were injected into the submucosa of tract and opening	27 of 33 patients with complete fistula healing at 8 wk 1 of 7 without complete healing had healing after 2nd dose 5 of 33 patients with > 50% closure	60% postoperative pain 19% anal pain -7% anal bleeding 1 patient with exacerbation of disease 1 patient with peritonitis from enteritis from CD	79% patients with complete closure after first dose
Cho et al[7]	2013	TS SS ES	Clinical Trial, Phase I Multi-center	10	Tract curettage was performed and internal opening was closed. Then, subcutaneous adipose tissue collected by liposuction was injected into the fistula tract wall and the surrounding internal opening	Group 1: Three patients with partial closure Group 2: Two patients with complete healing Group 3: One patient with complete healing, one with partial healing	13 AE in 7 patients which were not related to study drug: pain, diarrhea 2 patients SAE: enterocolitis, infliximab administration for new fistulas unrelated to target fistula	All patients with complete closure at 8 wk had sustained complete healing at 8 mo 50% patients after single injection with complete healing
Cho et al[8]	2015	TS SS ES	Clinical Trial, Phase II Multi-center	43	Tract curettage was performed and internal opening was closed. Then, subcutaneous adipose tissue collected by liposuction was injected into the fistula tract wall and the surrounding internal opening. This was done on a primary endpoint of 8 wk; then a retrospective clinical study was conducted looking at patient outcomes after 2 yr	41 of 43 patients were enrolled in the retrospective clinical study After excluded patient: 27 of 33 patients with complete closure	53 AE in 30 patients: abdominal pain (17.1%), eczema (9.8%) exacerbation of disease (9.8%), anal inflammation (7.3%), diarrhea (7.3%), fever (7.3%)	At 12 and 24 mo, respectively, 80% (P ≤ 0.0001) and 75% (P ≤ 0.001) of patients continued to have complete closure
Dietz et al[9]	2017	TS SS IS	Clinical Trial, Phase I Multi-center	12	Delivered ASC to the fistula through attachment of bioabsorbable matrix for surgical placement (MSC-MATRIX) through intraoperative placement	9 of 12 patients with complete healing at 3 mo 10 of 12 patients with compete healing at 6 mo	1 SAE from CD not study (debridement of granulation tissue of fistula tract) 2 AE: seromas at site of fat collection 11 AE: due to underlying CD	83.3% patients at 6 mo with complete healing after MSC-MATRIX placed

CD: Crohn’s disease; ASC: Autologous stem cells; TS: Transsphincteric; SS: Suprasphincteric; IS: Intersphincteric; ES: Extrasphincteric; RV: Rectovaginal; AE: Adverse events; SAE: Serious adverse events.

Table 2 Composite of autologous bone marrow derived stem cell therapy trials

Author	Year of study	Fistula site	Study population	Method of administration	Healing type of fistula	Safety	Outcome
Ciccocioppo et al[10]	2015	Perianal Enterocutaneous	10	Serial intrafistula injections of autologous bone marrow MSCs	2 patients with no recurrence of fistula at 5 yr	No adverse events	Fistula relapse free: 88% at 1 yr, 50% at 2 yr, and 37% during the following 4 yr

MSC: Mesenchymal stem cell.

Table 3 Composite of allogeneic adipose tissue derived stem cell therapy trials

Author	Year of study	Fistula site	Study population	Method of administration	Healing type of fistula (unhealed, partially, fully)	Safety	Outcome
García-Arranz et al[11]	2016	RV	10	Tract curettage was performed and vaginal or rectal flap added with intralesional injection of 20 million allogeneic adipose stem cells injected into the fistula tract and vaginal submucosa. If complete healing was not seen at 12 wk, patients were re-administered stem cells	2 patients with complete healing at 12 wk 2 patients with complete healing from the 8 patients with second administration of stem cells 9 patients at some point during the study had fistula healing	No SAE or AE	3 of 5 patients included in total (others excluded during study) remained healed at 52 wk, showing 60% efficacy
de la Portilla et al[12]	2013	Perianal	24	Intralesional fistula tract injection with stem cells with repeat administration at 12 wk with dose escalation if incomplete closure	38.1% patients achieved complete closure at week 12 65.3% patients achieved complete closure at week 24	13 patients with 32 AE and of these 5 were treatment related: anal abscess (3 patients), pyrexia (1 patient), uterine leiomyoma (1 patient)	69.2% patients had fistula reduction at 24 wk
Panés et al[13]	2016	TS SS IS ES	212	Patient randomized into two groups: Placebo with 24 ml saline Intralesional injection of Cx601 cells Study conducted over 24 wk	50% patients with Cx601 vs 34% placebo achieved complete fistula healing and remained closed at week 24 (P = 0.024)	TEAE: proctalgia, anal abscess, and nasopharyngitis 5% in treatment group and 6% in placebo group withdrew	Cx601 is effective and safe for treatment of refractory fistulizing CD
Panés et al[14]	2017	TS SS IS ES	212	This was a continuation of the above study from 24 to 52 wks Patient randomized into two groups: Placebo with 24 ml saline Intralesional injection of Cx601 cells	35%-40% patients withdrew before end of study 59.2% patients with Cx601 vs 41.6% patients with placebo (P = 0.013) achieved clinical remission 56.3% patients with Cx601 versus 38.6% patients with placebo (P = 0.010) achieved combined remission	TEAE: 76.7% in treatment group and 72.5% in control group: anal abscess/fistula 8.7% treatment group and 8.8% control group withdrew	Cx601 is safe and effective for treatment refractory complex perianal fistulas in patients with CD
Wainstein et al[15]	2018	TS IS Pouch-vaginal	9 (2 of 9 patients had 2 fistulas, so total fistula count was 11)	Two part study including: Examination under anesthesia, fistula mapping, drainage and seton placement Setons were removed 4-6 wks afterwards with ASC injected with biological plug formation	Complete healing in 10 of 11 fistulas Partial healing in 1 of 11 fistulas	No AE or SAE	Fistulizing disease can be treated successfully with a multi-approach treatment including ASCs, platelet rich plasma, and endorectal advancement flaps

CD: Crohn’s disease; ASC: Autologous stem cells; TS: Transsphincteric; SS: Suprasphincteric; IS: Intersphincteric; ES: Extrasphincteric; RV: Rectovaginal; AE: Adverse events; SAE: Serious adverse events; TEAE: Treatment emergent adverse event.

Table 4 Composite of allogeneic bone marrow derived stem cell therapy trials

Author	Year of study	Fistula site	Study population	Method of administration	Healing type of fistula (unhealed, partially, fully)	Safety	Outcome
Molendijk et al[1]	2015	Perianal	21	Patients assigned to four groups with curettage then intralesional fistula tract injection with stem cells or placebo (1) 1 × 107 (2) 3 × 107 (3) 9 ×107 (4) placebo	Week 24 fistula healing for groups (1) 66.7% (n = 5) (2) 85.7% (n = 5) (3) 28.6% (n = 5) (4) 33.3% (n = 6)	All patients reported pain and pus and/or discharge from fistula for 1 wk postoperatively One patient in each group (1, 2, 3, and placebo) developed perianal abscess	Use of intralesional injections of 3 × 107 was successful in fistula healing.

Table 5 Summary of all clinical trials evaluating stem cell therapy for fistulizing inflammatory bowel disease

Author	Year of study	Fistula site	Study population	Stem cell therapy	Method of administration	Healing type of fistula	Safety	Outcome
Sanz-Baro et al[16]	2015	RV Perianal	5	2 patients with Autologous ASC injected into fistula 3 patients with Allogeneic ASC injected into fistula	All 5 patients treated with either autologous or allogeneic ASCs and achieved remission who became pregnant were given data collection forms assessing age of treatment with ASCs, gestation age, gestational complications, any medication used during pregnancy for CD, type of delivery, fetal weight, and newborn malformations	2 of 5 patients with gestational complications of first term abortions, fetal growth restriction, and small for gestational age 1 of 4 patients who delivered with newborn malformations of syndactyly and clinodactyly	Two of the five patients experienced gestational complications: first trimester miscarriages, fetal growth restriction, and small for gestational age	No evidence that allogeneic or autologous ASC affects fertility in women

CD: Crohn’s disease; RV: Rectovaginal; ASC: Autologous stem cell.