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
Notice bibliographique
Résumé
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expansion was 254 (32-578). 3 patients received a dose of TR004 and attended all study visits, the other patient being withdrawn prior to dosing due to pregnancy after contraceptive failure.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.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,002 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».