Efficacy and Safety of Allogeneic Umbilical Cord-derived Mesenchymal Stem Cells for the Treatment of Complex Perianal Fistula in Crohn's Disease：A Pilot Study

doi:10.21203/rs.3.rs-2270943/v1

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Efficacy and Safety of Allogeneic Umbilical Cord-derived Mesenchymal Stem Cells for the Treatment of Complex Perianal Fistula in Crohn's Disease：A Pilot Study

https://doi.org/10.21203/rs.3.rs-2270943/v1

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published 31 Oct, 2023

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Objectives: The aim of the study was to evaluate the efficacy and safety of allogeneic umbilical cord-derived mesenchymal stem cells (TH-SC01) for complex perianal fistula in patients with Crohn’s disease (CD).

Methods: This was an open-label, single-arm clinical trial conducted at Jinling Hospital. Adult patients with complex treatment-refractory CD perianal fistulas (pfCD) were enrolled and received a single intralesional injection of 120 million TH-SC01 cells. Combined remission was defined as an absence of suppuration through an external orifice, complete re-epithelization, and absence of collections measured by magnetic resonance image scan (MRI) at 24 weeks after cell administration.

Results: A total of 10 patients were enrolled. Six patients (60.0%) achieved combined remission at 24 weeks. The number of draining fistulas decreased in 9 (90.0%) and 7 (70.0%) patients at weeks 12 and 24 respectively. Significant improvement in Perianal Crohn Disease Activity Index, Pelvic MRI-Based Score, Crohn Disease Activity Index, and quality of life score were observed at 24 weeks. No serious adverse events occurred. The probability of recurrence-free was 70% at week 52.

Conclusion: The study demonstrated that local injection of TH-SC01 cells might be an effective and safe treatment for complex treatment-refractory pfCD after conventional and/or biological treatments fail (ClinicalTrials.gov ID, NCT04939337).

Trial Registration: The study was registered in the Protocol Registration System ClinicalTrials.gov (NCT04939337).

perianal fistula

Crohn’s disease

umbilical cord

mesenchymal stem cell

Crohn’s disease (CD) is a complex, chronic disorder that primarily affects the digestive system. CD involves an abnormal immune response that causes excess inflammation. Anal fistula is the most common complication of CD¹. CD perianal fistula (pfCD) is often treatment refractory, with frequent recurrences. pfCD imposes a signiﬁcant economic burden on patients and impairs their quality of life. Treating pfCD requires multidisciplinary teamwork combining medication and surgery². Recently biological agents, such as Inﬂiximab, Certolizumab pegol, and Ustekinumab, have achieved a high rate of ﬁstulae closure³. However, recurrence is still a challenge. The closure rate of pfCD after Inﬂiximab treatment was 63% at week 14, but decreased to 36% at week 54.⁴ For ustekinumab, it was roughly 40% at 6 months.⁵ Remission can only be achieved in half of the cases even with optimal surgical and biological therapy⁵^,⁶.

Mesenchymal stromal cells (MSCs) are defined as a plastic-adherent cell population that can be induced to differentiate in vitro into cells of osteogenic, chondrogenic, and adipogenic lineages. MSCs can exert immunomodulatory and anti-inﬂammatory function by secreting a variety of bioactive molecules and regulating local immune response^{7, 8}. In 2003, Garcia-Olmo reported autologous MSCs were effective for recurrent rectovaginal ﬁstula in a female CD patient⁹. In March 2018, allogeneic, expanded, adipose-derived stem cells (Darvadstrocel) were approved by the European Medicines Agency for the treatment of complex perianal fistulas in adult patients with non-active/mildly active luminal CD¹⁰.

Although MSCs can be readily harvested from adipose tissue, liposuction is an invasive surgical procedure. Umbilical cord (UC) is an attractive alternative to adipose. Compared to MSCs derived from adult adipose, UC-MSCs may be cultured longer and have higher proliferation capacity¹¹. A substantial number of UC-MSCs can be produced after several passages. Isolation of UC-MSCs is ethically acceptable as UC is considered to be medical waste. Moreover, UCB-MSCs exhibited a greater anti-inflammatory effect than adipose-derived MSCs^12-14.

We conducted a single-arm, pilot study to evaluate the safety and effects of TH-SC01, an investigational, allogeneic, umbilical cord-derived, off-the-shelf MSC product candidate, to treat patients with pfCD that was refractory to conventional and/or biological treatments. We hypothesized that UC-MSCs locally injected into perianal fistulas were safe and effective at the end of the 24-week follow-up and could increase the health-related quality-of-life scores.

This was a prospective single-arm pilot study conducted at Jinling Hospital, a tertiary care academic hospital in Nanjing. Patients were enrolled from November 2020 to November 2021. We included patients who were 18 years of age or older and fulfilled the Committee of the American Society of Colon and Rectal Surgeons 2016 diagnostic criteria for complex pfCD; and had non-active or mildly active luminal CD defined as Crohn’s Disease activity index (CDAI)<220, with a minimum duration of 6 months. In addition, they had to have received surgical therapy (drainage or seton placement) and systemic administration of anti-TNF-alpha for at least 14 weeks. Patients with more than 1 internal and 3 external openings, abscess, stenosis, severe proctitis, active infections or lymphoproliferative active diseases were excluded. Patients who were allergic to anesthetics or magnetic resonance image scan (MRI) contrast were also excluded. The clinical trial process is shown in Figure 1.

Production of GMP-Grade human UC-MSCs

TH-SC01 is a cellular product manufactured in a Good Manufacturing Practice (GMP) facility at TopCel Biopharmaceutical (Nanjing, China). Umbilical cord tissue was donated by a healthy volunteer whose baby was delivered by elective cesarean section. Informed consent was obtained before cesarean section.

Briefly, cord tissue was placed in a sterile bottle containing DMEM/F12, and transported to the GMP facility. After umbilical vessels were removed, Wharton’s jelly was sliced into fragments of about 1 cm in length. The fragments were placed on culture plates in DMEM/F12 media with 1% platelet lysate (AventaCell BioMedical Corp, Atlanta, USA). After about 15 days, cord fragments were discarded and cells were digested with GMP-grade enzymes (Gibco Life Technologies, Waltham, USA). Cells were subsequently passaged. UC-MSCs of passage 3 were used as a source to produce a master cell bank (MCB) and cryopreserved in cryovials in the vapor phase of liquid nitrogen. For quality control, karyotyping and viral tests were done. Karyotype analysis confirmed a normal human karyotype. UC-MSCs were also evaluated for cell surface markers CD44, CD73, CD90, CD105, CD31, CD34, and CD45. We thawed cells for subculture under the same conditions. Cells cultured to passage 5 were used in the present study.

The final cells were harvested into a solution with 5% human serum albumin. Release testing included total nucleated cell count, viability, endotoxin, and pathogens (human immunodeficiency virus-1 and 2, cytomegalovirus, hepatitis B virus, hepatitis C virus, human T lymphocytic virus, Epstein-Barr virus, and mycoplasma). Pathogens were detected using reverse transcriptase PCR. For each patient, 120 million cells were formulated in 24 mL and supplied in four vials (6 mL/vial). Cells were shipped to the hospital on the day of administration. The formulated product can be stored for a maximum of 48 between 4°C and 8°C.

Treatment procedure

A pelvic MRI scan was done at the screening to guide the surgical procedures and to assess abscesses. Two weeks before cell administration, patients might be treated with fistula curettage and seton placement under anesthesia.

If a seton was placed, it was withdrawn immediately before cell administration. Closure of the internal opening was done using polyglactin absorbable 2/0 stitches and was confirmed by injection of 10 mL saline solution through the external opening. Subsequently, 120 million cells were injected with a 22G needle into tissue adjacent to all fistula tracts and the internal opening. This dose was selected according to the studies with Darvadstrocel. Half of the cells were injected via the anal canal into the tissue surrounding the sutured internal opening, and the other half of cells were injected through the external opening (s) into the fistula walls (no deeper than 2 mm) along the fistula tract (s) (Figure 2).

During the study, patients could be treated with antibiotics. Immunomodulators and anti-TNF mAbs were maintained at stable doses. A steroid course was permitted to treat occurrences of luminal disease during the study, with a starting dose of 40 mg tapered over a maximum of 12 weeks.

Patients were followed at weeks 1, 2, 4, 12, 24 and 52. Outcomes were assessed by masked investigators at baseline and all study visits. Pelvic MRI was performed at 12 weeks and 24 weeks¹⁵.

Outcomes

The primary endpoint was combined remission at weeks 24, defined as no draining in all treated external openings despite gentle finger compression, and the absence of collections larger than 2cm of the treated perianal fistulas in at least two of three dimensions by MRI.

There were two key secondary endpoints: clinical remission and clinical response. Clinical remission was defined as closure of all treated external openings that were draining at baseline despite gentle finger compression by week 24. Clinical response was defined as closure of at least 50% of all treated external openings that were draining at baseline by week 24.

Other secondary endpoints were Perianal Crohn’s Disease Activity Index (PDAI)/CDAI score, VAS score for pain, and quality of life by the Inflammatory Bowel Disease Questionnaire (IBDQ), and MRI-based Van Assche score at weeks 12 and 24.

We monitored adverse events, particularly exacerbations of symptoms, using a standard adverse-event case report form at each visit.

Statistical analysis

Categorical variables were described as frequencies, percentages, and ordinal and continuous variables, with the median and min-max range. The Wilcoxon test was used to compare the baseline and final results of the PDAI, Van Assche score, CDAI, and IBDQ. A two-sided P value of less than 0.05 indicated statistical significance.

Baseline Characteristics of the Patients

Fourteen patients were screened and ten were enrolled. The average age was 34.3 years (range, 22-53). Eight were male. Mean durations of CD and fistula were 5 years (range, 2-15) and 4 years (range, 1-12) respectively. The numbers of fistula tracts were one (n=3), two (n=6), and three (n=1) respectively, and the numbers of external openings were one (n=4), two (n=5), and three (n=1) respectively (Table 1).

Clinical outcomes

Sixty percent (6/10) of patients achieved combined remission at 24 weeks. Ninety percent (9/10) and seventy percent (7/10) of patients had a clinical response at 12 weeks and 24 weeks respectively (Table 2). Two patients had complete occlusion of fistula tracts on MRI at 24 weeks (Figure 3). Seven patients with clinical response at 24 weeks did not recur at 52 weeks.

There were 17 external fistulas in 10 patients, and 13 were closed and epithelialized at 12 weeks. The external fistula recurred in two patients at 24 weeks (Table 2).

Overall, a signiﬁcant reduction of the PDAI score was observed after MSCs administration. Van Assche scores demonstrated a signiﬁcant reduction from the 12th week. Although CDAI scores were all less than 220, the reduction was also signiﬁcant. In addition, IBDQ increased during follow-up (Figure 4).

During the study, no patient received steroids for a flare of CD. No patient received antibiotics or anti-TNF treatment as a rescue treatment for fistula.

Safety

Three patients had adverse events, which were perianal pain and low fever, elevated liver enzymes, and perianal pain respectively. All adverse events were resolved within a week.

Symptomatic pfCD is a devastating complication. In this pilot study, the number of draining fistulas decreased in most patients (90%) at 12 weeks after UC-MSCs administration. More than half of patients (60%) showed closure of all treated external openings at 24 weeks and did not recur during the 1-year follow-up. All patients reported significantly improved quality of life.

As pfCD is characterized by increased inflammation that impedes epithelial healing¹⁶^,¹⁷, the underlying mechanism of MSCs might mainly involve their immunomodulatory ability. MSCs are capable of regulating the functions of a diverse array of cells in the immune system. MSCs can interact with B lymphocytes, T lymphocytes, NK cells, monocyte-derived dendrite cells, and neutrophils, affecting differentiation and activation of immune cells^{18, 19}. In animal models, MSCs have been shown to decrease a wide panel of inﬂammatory cytokines and chemokines and increased interleukin-10 levels, directly acting on activated macrophages²⁰. These pre-clinical data are consistent with the observed clinical outcomes with MSCs for pfCD and CD.

The preliminary results showed that UC-MSCs might be superior to ASCs at the same cell dose²¹ In the phase 3 trial, Panés et al reported that the combined remission rate was 50% (53/107), while it was 60% (6/10) in our study²². Although MSCs from different tissues have similar surface antigen expression, their biological attributes are different, especially their immunomodulatory activity. For example, Najar et al showed that in mixed leukocyte reactions (MLRs) using irradiated allogeneic peripheral blood mononuclear cells (PBMCs) as stimulating cells to activate T-lymphocytes, MSCs from bone marrow, umbilical cord, and adipose tissue each induced suppression of T-cell alloproliferation in an MSC concentration–dependent manner²³. MLR suppression by UC-MSCs was more extensive than that observed with the other two sources. In accordance with this, UC-MSCs secreted more leukemia inhibitory factor, a cytokine that promotes an anti-inflammatory phenotype in several types of immune cells,²⁴ into the supernatants than did adipose tissue-derived MSCs.²⁵ Li et al reported that PHA/IL-2-induced T cell proliferation decreased to 35.5±1.7% and 22.6±0.9% in the presence of AT-MSCs and WJ-MSCs, respectively. The results from Transwell culture were similar to those of the contact culture. Thus, the inhibitory effect of WJ-MSCs was more prominent than that of AT-MSCs¹⁴. Similarly, Ayatollahi et al co-cultured MSCs with allogeneic phytohemagglutinin (PHA) activated PBMCs¹³. The growth suppression was also assessed indirectively by using Transwell culture system. They found the proliferation of PBMCs was reduced by 6.2 folds and 7 folds in cultures with adipose-derived MSCs and UC-MSCs respectively compared to the PHA-activated cells. When the indirect growth suppression was assessed by using the Transwell culture system, adipose-derived MSCs and UC-MSCs caused growth reduction of PBMCs by 3 folds and 8 folds respectively compared to the PHA-activated cells.¹³ Thus, compared with adipose-derived MSCs, human UC-MSCs have a greater ability for immune regulation. Additionally, UC-MSCs have stronger proliferation. Wang et al reported that UC-MSCs growth was arrested by passages 17-18, and adipose tissue-derived MSCs proliferation ended by passages 11-12²⁶. A comparison of the clonogenic potential of the different tissue MSCs, by colony forming unit-fibroblast assay, showed that by passage 3, more colonies formed from UC-MSCs (25.7 ± 8.9) than from adipose tissue-derived MSCs (18.4 ± 4.6). Therefore, UC-MSCs might become the preferred choice of stem cells for anal fistula.

Although anti-TNF monoclonal antibody treatment provides a new option for the management of Crohn's fistula⁴, some patients cannot achieve complete healing. In a clinical study with infliximab, only 36 percent of patients in the infliximab maintenance group had a complete absence of draining fistulas at week 54²⁷. In addition, there is a high recurrence rate during maintenance therapy²⁸. The sustained response in this study seems to be greater than that of the previous reports with anti-TNF monoclonal antibody^29-31. In our study, patients who failed to Infliximab for more than 12 weeks were enrolled and MSCs still showed a promising good outcome. Given that recurrence is common in patients with pfCD, our study has important implications. It is worth noting that fistula exudation reappeared in two patients at 24 weeks, who showed closure of all treated external openings at week 12. We propose that a second dose of MSCs might improve the long-term effects³².

We found the improvement of MRI score was not parallel to remission of clinical symptoms. Clinical symptoms began to alleviate about 7 days after cell injection, while significant improvement shown by MRI only appeared about 12 weeks later. Therefore, MRI exanimation in the follow-up may be performed after 12 weeks.

Most recently, the American Society of Colon and Rectal Surgeons published clinical practice guidelines on the management of anorectal abscess, fistula-in-ano, and rectovaginal fistula and recommends that for select patients with Crohn’s disease who have refractory anorectal fistulas, local treatment with MSCs are considered effective and safe³³. The recommendation was based on several phase I, phase II, and phase III clinical trials with bone marrow-derived and adipose-derived MSCs^{22, 34-39}. Our study provides further evidence that MSCs from another source, i.e, umbilical cord, is safe and effective for pfCD. The optimal therapeutic goals for the treatment of Crohn's fistulae are complete healing of the lesions without recurrence and no injury to the anal sphincter. Surgery including incision, drainage and placement of loose (draining) setons may result in fecal incontinence ranging from 30 to 40 %^{29, 40}. In this context, MSC therapy could be a promising treatment option for pfCD refractory to conventional therapy.

In conclusion, our preliminary findings demonstrated local UC-MSCs treatment produced a favorable therapeutic outcome and had a good safety profile in patients with pfCD for longer than 24 weeks. Randomized controlled trials involving larger clinical samples are warranted to assess the generalizability of our findings. Also, more mechanical studies are needed to deepen our understanding of this promising therapeutic approach.

CD, Crohn’s disease; pfCD, CD perianal fistulas; MRI, magnetic resonance image; MSCs, Mesenchymal stromal cells; UC, Umbilical cord; CDAI, Crohn’s Disease activity index; PDAI, Perianal Crohn’s Disease Activity; GMP, Good Manufacturing Practice; MCB, master cell bank; IBDQ, Inflammatory Bowel Disease Questionnaire; MLRs, mixed leukocyte reactions; PBMCs, peripheral blood mononuclear cells; PHA, phytohemagglutinin.

Acknowledgements

Not applicable.

Authors’ Contributions

(I) Conception and design: JW and YFZ; (II) Provision of study materials or patients: CCY, ZY, QJ and JJF; (III) Collection and assembly of data: XYF, JF and JX; (IV) Data analysis and interpretation: GH, LML and YFW; (V) Manuscript writing: All authors; (VI) Final approval of manuscript: All authors.

Funding

This work was supported by the National Natural Science Foundation of China (No. 81873559). The funding bodies played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Availability of data and materials

The datasets during and analysed during the current study available from the corresponding author on reasonable request.

Ethics approval and consent to participate

The study was approved by the Ethics Committee of Jinling Hospital, Medical School of Nanjing University (project title: Efficacy and Safety of Allogeneic Umbilical Cord-derived Mesenchymal Stem Cells for the Treatment of Complex Perianal Fistula in Crohn's Disease; approval number: 2020DZWJWKT-003; date of approval: 31 August 2020).

Consent for publication

Not applicable.

Competing interests

TH-SC01 is a cellular product manufactured by TopCel Biopharmaceutical. All authors declare no competing interests.

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Table 1 Demographic and baseline characteristics

Variable	UC-MSCs (n=10)
Male (%)	8 (80)
Age (years)	34.3 (22-53)
Median BMI (range)	22(18-23)
Median CD duration, y (range)	8(2-18)
Median fistula duration, y (range)	5(1-16)
History of surgery for fistula, n (%)	7 (70)
Fistulas prior treatment failure Antibiotics Anti-TNF	8 2
Number of fistula tracks 1 2 3	3 6 1
Number of external openings 1 2 3	4 5 1
Location Extra-sphincteric Inter-sphincteric Supra-sphincteric Trans-sphincteric	2 5 2 1
Extension Infraelevator Supraelevator	6 4
Rectum wall involvement Normal Thickened	3 7

Table 2 Efficacy results

Variable	n
Combined remission at 24 weeks
No	4
Yes	6
Closure of external openings after 12 weeks No Yes (at least 1)	1 9
MRI absence of collections >2 cm after 12 weeks No Yes (at least 1)	1 9
Closure of external openings after 24 weeks No Yes (at least 1)	3 7
MRI absence of collections >2 cm after 24 weeks No Yes (at least 1)	3 7
Subjects presenting luminal relapse after 24 weeks No Yes	9 1

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Efficacy and Safety of Allogeneic Umbilical Cord-derived Mesenchymal Stem Cells for the Treatment of Complex Perianal Fistula in Crohn's Disease：A Pilot Study

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