P999 First in human treatment of Crohn’s disease with autologous ex-vivo expanded polyclonal, gut-targeted regulatory T cells: Initial results of the TRIBUTE feasibility study
Authors: Irving P M , Seah D , Centritto A , Clough J , Canavan J , Goldberg R , Prevost A T , Vasconcelos J C , Lyne M , Palmer Joyce J , Patel P , Tasker S , Marks P , Rodger B , Jackson I , Macallan D , Ong M , Sutcliffe M , Travis M , Lord G 
Published: January 2024

Abstract

Background
Despite the increase in novel medications for Crohn’s disease (CD), many patients either fail to respond adequately to, or are intolerant of current drugs. Cell therapies have yet to have a significant impact in IBD but represent a potential novel treatment option. Regulatory T-cells (Tregs) play a key role in immune homeostasis, and Treg dysfunction is implicated in the pathogenesis of CD. Their therapeutic potential has not been assessed in humans with CD. We designed a Phase 1b study to explore the feasibility of using novel, autologous, ex-vivo expanded, gut-homing Tregs as a treatment for CD.

Methods
The TRIBUTE feasibility study aimed to treat 4 patients with treatment-refractory, moderate to severe CD (CDAI 220-450 and endoscopic ulceration) with a single dose of 3-5x106 cells/kg of TR004, an autologous cell product comprising CD4+CD25+CD127lowCD45RA+ Tregs expanded ex-vivo in the presence of an agonist that increases the expression of a4b7, priming the cells for gut homing. Deuteration during expansion allowed for cell tracking. Primary outcomes were dose-limiting toxicity by week 5, feasibility of recruitment to and retention in the study, successful expansion of the cells and successful dosing. Colonoscopy was performed at screening and at week (wk) 8 and disease activity (CDAI and biomarkers) was assessed at wk 0,1,2,3,5 and 8. Safety follow up is planned to wk 104.

Results
5 patients (3 male, median age 36 (range 24-39), median failed advanced therapies 3 (2-4)) were screened. In 1 patient, cells failed at day 21 of expansion due to human error requiring the patient to be replaced.
Of the 4 patients with successful expansion of cells, after 23-30 days of expansion, median b7 expression was 98% (92-99%) and cell viability was 91% (84-94%). Median fold expansion was 254 (32-578). 3 patients received a dose of TR004 and attended all study visits, the other patient being withdrawn prior to dosing due to pregnancy after contraceptive failure. No dose-limiting toxicities occurred. 1 patient, with long standing colonic CD and PSC, had dysplasia identified at the wk 8 colonoscopy and underwent colectomy at wk 20. 1 patient started oral prednisolone at wk 6 for active disease. In the 3 patients who were dosed, median CDAI was: wk0: 357, wk1: 295, wk2: 207, wk3: 218, wk5: 200 and wk8: 208. (Figure 1a). SES-CD was unchanged from screening to week 8 (Figure 1b).

Conclusion
In this first in human study we demonstrated that treatment with a novel cell product comprising autologous, ex-vivo expanded, gut-homing Tregs, is feasible in patients with CD. No dose limiting toxicity was identified. Clinical and endoscopic changes should be interpreted with caution in such small numbers of patients. There is a rationale to proceed to Ph2.