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
Bibliographic record
Abstract
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expansion was 254 (32-578). 3 patients received a dose of TR004 and attended all study visits, the other patient being withdrawn prior to dosing due to pregnancy after contraceptive failure.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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".