Editorial
Stem Cell Transplantation for Treatment of Crohn's Fistulae
Fernando de la Portilla*
Department of General and Digestive Surgery, University of Seville, Spain
*Corresponding author: Fernando de la Portilla, Department of General and Digestive Surgery, “Virgen del Rocío” University Hospital/ IBiS/CSIC/University of Seville, Seville, Spain
Published: 09 Feb, 2017
Cite this article as: de la Portilla F. Stem Cell
Transplantation for Treatment of
Crohn's Fistulae. Clin Surg. 2017; 2:
1296.
Editorial
Up to 20% of patients with Crohn's disease (CD) may have perianal fistula disease, which is
frequently associated with perianal collections [1]. Classically, surgery has played an important role,
by the placement of drains or setons creation of ostomies, and in severe cases, even proctectomy [2].
However, in recent years, medical treatment with or without the temporary placement of drains, has
taken a leading role. Immunosuppressants such as azathioprine, 6-mercaptopurine, methotrexate,
and cyclosporine have proven beneficial in many patients. In more complicated cases where these
drugs are ineffective, biological treatments based on monoclonal antibodies have been shown to
have some success for the induction and maintenance of remission of perianal fistula disease and
associated proctitis [3]. Still, the percentage of patients who do not respond or do so only partially
remain significant. Furthermore, the existence of serious complications associated with treatment
should not be overlooked [4].
It is as a result of these inadequacies in current treatment strategies that cell therapy has arisen as
a complementary option [5]. The promising results published in recent years, both with autologous
and in allogeneic cells, highlight a need for greater understanding of the basic principles of this new
route, and for clarification of the current state of the topic.
Adult stem cells can be obtained using much simpler methods, and have no restrictions or
ethical considerations. Furthermore, because of their autologous origin, they are not immuno
reactive. Early studies using adult stem cells have focused on mesenchymal stem cells (MSCs). These
can be found in the stroma of virtually every organ, for example, in subcutaneous adipose tissue and
bone marrow. Being fibroblastoid cells, they are the precursors of all types of non-haematopoietic
connective tissues (bone, fat, cartilage, etc.). MSCs are generally obtained by selection through
adherence to tissue culture plastic, as they are able to adhere and grow in conditions where other
cell types do not usually proliferate [6].
MSCs have a high capacity for proliferation and differentiation. Furthermore, under certain
experimental conditions, they have displayed the ability to differentiate into non-connective cell
lineages, such as neuronal and endothelial. Finally, as a particularly interesting property for the
use at hand, they are capable, both in vitro and in vivo, of inhibiting immune response. This ability
to immuno regulate includes inhibition of the activation of T-, B-, and NK-cells, the maturation
of dendritic cells, as well as protecting against inflammatory and/or autoimmune pathologies,
including transplant rejection [7].
The precise mechanism of the therapeutic action of MSCs is not fully understood, but is likely
to reflect their inherent characteristics, in particular their differentiation potential [8]. MSCs have
the ability to migrate to the site of a lesion or inflammatory process, stimulate the proliferation and
differentiation of resident stem cells through the secretion of growth factors, remodel the matrix,
and exert an immunomodulatory and anti-inflammatory effect. Together, these properties aid
help the healing of tissues [9]. It has also been demonstrated that MSCs can induce an increase in
epithelialisation and angiogenesis through a process of differentiation and paracrine interaction
with skin cells [10].
The first experience with stem cells in the treatment of anal fistulae was reported by Garcia-
Olmo et al. [10]. Several studies have since been published, the majority of which are from Spanish
groups. The MSCs used have mainly originated from adipose tissue, with only two studies using
bone marrow MSCs. In these latter cases, both allogeneic and autologous cells have been used. In all
studies, administration was intralesional, with fibrin glue often used [12].
Today, any questions as to the feasibility and safety of such treatment seem to have been
resolved, at least within the range of doses used. A retrospective study
evaluating whether MSC treatment has any influence on fertility,
course of pregnancy, birth weight, or physical status was recently
published [13]. Five patients with fistula associated with Crohn's
disease treated with ASCs, and who indicated their intention to
have children after completion of treatment, were tracked. Fertility
and pregnancy course were not found to be affected by this therapy.
Furthermore, no treatment-related malformations in newborns were
observed. Therefore, it was concluded that in the patients analysed
in the study, local injection of ASCs was not associated with adverse
effects on the ability to conceive, pregnancy course, or the newborn's
condition.
In the published literature there are differences in cure rate
depending on the follow-up, but in general it is estimated to be
between 50 and 70%.
Ciccocioppo et al. [12] evaluated the long term safety and efficacy
of the use of bone-marrow-derived MSCs. In their study, 8 patients
were followed prospectively for 72 months. These patients were part
of a phase I/II trial previously conducted, in which a cure rate of 70%
per year was reported, with improvement observed in the remaining
30%. Patients received serialised injections of MSCs (4 on average)
at intervals of 4 weeks. Secondary endpoints were the time patients
remained without fistula and the time they were free of medical or
surgical treatment. The Chrohn’s Disease Activity Index (CDAI)
increased over the first two years, followed by a gradual decline in
the third year, and stabilisation at the end of follow-up at figures
similar to those of the first year. The probability of remaining without
fistula was 88% for the first year, 50% at two years, and 37% over the
next four years. The probability of patients being free from surgery
was 100% for the first year, 75% for years 2 to 4, and 63% at years
5 and 6. Finally, the probability of patients being free from medical
treatment was 88% for the first year, 25% at years 2 to 4, and 25% at
years 5 and 6. No adverse effects related to treatment in these followup
periods were recorded. The authors conclude that the fact that the
activity indices increase again in the second year might suggest that
this therapy is not curative, but that it does improve the remission
rate in patients with refractory disease. Moreover, almost all patients
required the reintroduction of biological or immunosuppressive
therapy after the second year [12].
The safety and feasibility of local eASC administration has been
demonstrated in Phase I/IIa study in which Cx601 was injected at
doses of 20 million cells with an additional dose of 40 million cells
in case of incomplete fistula closure at Week 12, without apparent
safety signals. This trial (in which only one tract was treated) showed
that a percentage of patients not responding to 20 million cells could
be healed with an additional higher dose of 40 million cells 12 weeks
after the first dose [14].
Recently we are published the results of a phase III, randomised,
placebo, double-blind, multicentre, and international clinical trial
employing Cx601, a preparation of allogeneic ASCs. Cx601 was
statistically superior to placebo in achieving the combined response
(clinical and imaging) of complex perianal fistulas in Crohn's disease
patients whose response to previous treatment, including anti-TNFs,
had been inadequate. The follow up was 24 week [15].
There is no doubt that a new avenue has opened for the treatment
of Crohn’s disease patients suffering from fistulae refractory to
conventional therapy. Since the first description of the treatment,
interest in this therapy has grown, so that in addition to the 11 studies
published to date, at the time we write this chapter, there are more
than a dozen clinical trials in recruitment or in the results publication
phase. While the safety of ASC therapy seems to have been well
established, the optimal dosage, route of administration (intravenous
versus intralesional), administration technique (alone or together
with fibrin glue), among other matters, are yet to be adequately
determined. However, these should be investigated and resolved in
the coming years.
References
- Schwartz DA, Loftus EV, Tremaine WJ, Panaccione R, Harmsen WS, Zinsmeister AR, et al. The natural history of fistulizing Crohn’s disease in Olmsted Country, Minnesota. Gastroenterology. 2002; 122: 875-880.
- Singh B, George BD, Mortensen NJ. Surgical therapy of perianal Crohn’s disease. Dig Liver Dis. 2007; 39: 988-992.
- Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA, et al. Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med. 1999; 340: 1398-1405.
- Baert F, Noman M, Vermeire S, Van Assche G, D' Haens G, Carbonez A, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med. 2003; 348: 601-608.
- García-Olmo D, García-Arranz M, Herreros D, Pascual I, Peiro C, Rodríguez-Montes JA. A phase I clinical trial of the treatment of Crohn’s fistula by adipose mesenchymal stem cell transplantation. Dis Colon Rectum. 2005; 48: 1416-1423.
- Verfaillie CM. Adult stem cells: assessing the case for pluripotency. Trends Cell Biol. 2002; 12: 502-508.
- García-Gómez I, Elvira G, Zapata AG, Lamana ML, Ramírez M, Castro JG, et al. Mesenchymal stem cells: biological properties and clinical applications. Expert Opin Biol Ther. 2010; 10: 1453-1468.
- Gimble, JM, Katz AJ, Bunnell BA. Adipose-derived stem cells for regenerative medicine. Circ. Res. 2007; 100: 1249-1260.
- Yoo KH, Jang IK, Lee MW, Kim HE, Yang MS, Eom Y, et al. Comparison of immunomodulatory properties of mesenchymal stem cells derived from adult human tissues. Cell. Immunol. 2009; 259: 150-156.
- Wu Y, Chen L, Scott PG, Tredget EE. Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells. 2007; 25: 2648-2659.
- García-Olmo D, García-Arranz M, García LG, Cuellar ES, Blanco IF, Prianes LA, et al. Autologous stem cell transplantation for treatment of rectovaginal fistula in perianal Crohn's disease: a new cell-based therapy. Int J Colorectal Dis. 2003; 18: 451-454.
- Ciccocioppo R, Bernardo ME, Sgarella A, Maccario R, Avanzini MA, Ubezio C, et al. Autologous bone marrow derived mesenchymal stromal cells in the treatment of fistulising Crohn’s disease. Gut. 2011; 60: 788-798.
- Sanz-Baro R, García-Arranz M, Guadalajara H, de la Quintana P, Herreros MD, García-Olmo D. First-in-Human Case Study: Pregnancy in Women With Crohn's Perianal Fistula Treated With Adipose-Derived Stem Cells: A Safety Study. Stem Cells Transl Med. 2015; 4: 598-602.
- de la Portilla F, Alba F, García-Olmo D, Herrerías JM, González FX, Galindo A. Expanded allogeneic adipose-derived stem cells (eASCs) for the treatment of complex perianal fistula in Crohn’s disease: results from a multicenter phase I/IIa clinical trial. Int J Colorectal Dis 2013; 28: 313-323.
- Panés J, García-Olmo D, Van Assche G, Colombel JF, Reinisch W, Baumgart DC, et al. ADMIRE CD Study GroupCollaborators.. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial. Lancet. 2016; 388: 1281-1290.