LB3 - E-CEL UVEC Cell Therapy for the Treatment of Cryptoglandular Peri-Anal Fistula

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Purpose/Background: Cryptoglandular peri-anal fistulas rarely heal spontaneously and often need treatment. Fistulotomy has high cure rates but carries a 5-15% risk of anal incontinence. Surgeons and patients seek safer, more effective alternatives, which can be performed in-office and still allow subsequent fistulotomy if needed. E-CEL human umbilical vein endothelial cells (UVEC) are allogeneic, E4ORF1+ cells produced under FDA GMP regulations. Animal models demonstrated that E-CEL UVEC helps promote the natural healing process and tissue regeneration. E4ORF1 gene is a non-toxic pro-survival gene isolated from adenovirus; its insertion boosts metabolism and enhances the regenerative potential of umbilical vascular endothelial cells. We hypothesize that peri-anal fistula can be safely treated with E-CEL UVEC injections with a clinically acceptable success rate.

Methods/Interventions: An open-label dose-escalating Phase 1b study protocol was developed, cleared by the FDA via an IND, and approved by the Weill-Cornell IRB as an investigator-initiated trial. Initially, 6 adult subjects received E-CEL injections into the fistulotomy wound (Cohort A). Subsequently in Cohort B (no fistulotomy), 23 adult subjects (19-77yo, 60% female/40% male) received E-CEL injection treatment at a dose of 15x10^cells/cm along the tract and 15x10^6 cells into the internal opening. 9 subjects received a single treatment (Cohort B1), whereas14 subjects received 4 treatments over 9 to 12 weeks (Cohort B2). The final study visit occurred at Week 24. Patients were monitored for a complete response, defined as the resolution of the symptoms and full healing and closure of both the external and internal openings of the fistula tract.

Results/Outcomes: Cohort A all healed within 12-24 weeks. Surgical assessment tended to favor acceleration and improved quality of the healing tissue. No adverse event occurred. For Cohort B: 9 B1 subjects and 10 B2 subjects completed the week 24 visit. The complete response for the B1 cohort was 22% (2/9) versus 50% (5/10) for the B2 cohort. Responders in the B2 cohort achieved healing within week 12. 33% were partial responders in the B1 cohort vs 50% for B2. Most of the partial responders in the B2 cohort have postponed definitive fistulotomy because of a decrease in the size of the fistula and/or improvement in fistula symptoms. In the B1 cohort, 22% of cases were refractory, compared to 0% in the B2 cohort. One adverse event, a severe vasovagal reaction, occurred but was self-limited. It was prevented in subsequent treatments through pre-treatment oral sedation.

Conclusion/Discussion: This report is the first to demonstrate that multiple fine-needle injections of E-CEL cells can heal cryptoglandular peri-anal fistulas safely, mainly in an office setting, achieving 50% success, without surgical intervention by 12 weeks. Our recent ASCRS membership survey (n=223) demonstrated that the natural healing rate of peri-anal fistulas was estimated to be 3-5% (median), and a healing rate of 40-50% would be the criteria for routine adoption by colorectal surgeons. A multi-center, randomized Phase 2 study is warranted for further investigation of this novel approach to treating intractable peri-anal fistulas.