“First-In-Human” Clinical Trial Employing Adoptive Transfer of Autologous Thymus-Derived Treg Cells (thyTreg) to Prevent Graft Rejection in Heart-Transplanted Children
Notice bibliographique
Résumé
Immune allograft rejection remains the main obstacle to reach successful transplants. Transfer of regulatory T cells (Treg) has acquired growing interest in attempts to prevent rejection. However, the limited number and the differentiated phenotype of Tregs isolated from blood constitute important drawbacks for the effectiveness of this strategy. In collaboration with several teams, we have explored the use of the thymic tissue, which is routinely discarded during pediatric cardiac surgery, as an alternative source of Tregs to be used as cellular immunotherapy in heart-transplanted children. Material and Methods We developed a novel GMP-compatible protocol to obtain massive amounts of thymus-derived Tregs (thyTreg) from thymuses discarded from infants (<3 years old). Several quality tests were performed on the final thyTreg cell product. A “first-in-human” clinical trial (phase 1/2a) will be initiated in January 2018 to test the safety, feasibility and effectiveness of the adoptive transfer of autologous thyTregs in heart-transplanted children. Results/Discussion ThyTreg purified from thymuses were activated and cultured ex-vivo for 7–10 days with our protocol, and the final product showed a very high purity, with >95% of CD25+Foxp3+ cells, and a viability >90% (Fig 1). Importantly, the number of thyTreg cells obtained from one single thymus reached values of more than 13x109 (billions) cells. Considering the Treg doses employed in previous clinical trials (1–10 x106 Treg/kg), in the case of transplanted infants, this amount will be enough to prepare more than 1000 doses of thyTreg treatment. The final product of thyTreg showed great expression of CTLA-4, CD39, HLA-DR and Helios. In comparison to blood-derived Tregs, the frequency of IL-10-secreting cells was markedly higher in thyTregs (Fig 2). Besides, the final thyTreg product showed a very high suppressive capacity, decreasing the proliferation of CD4+ and CD8+ T cells by more than 80% (Fig 3). The thyTreg product will be employed as immunotherapy to prevent rejection in a clinical trial. Infants younger than 3 years old included in the waiting list for a heart transplant will be enrolled. A single dose of autologous thyTreg cells purified from the thymus discarded in the surgery will be infused back to the children at day +10 post-transplant, when doses of immunosuppressants are reduced (Fig 4). The rest of the thyTreg doses will be cryopreserved in a Biobank for potential reinfusions in the future to the patient. Conclusion Massive quantities of highly suppressive and pure Thy-Tregs obtained with our novel GMP-compatible protocol are suitable to be employed as cellular immunotherapy to prevent rejection in heart-transplanted children. At the beginning of 2018, we will initiate the first clinical trial to test the safety of the procedure, the feasibility and the effect of the thyTreg therapy in the context of solid organ transplantation.Grant from Instituto de Salud Carlos III (ISCIII) co-financed by FEDER funds (PI15/00011). Grant from Instituto de Salud Carlos III (ISCIII) co-financed by FEDER funds (ICI14/00282).
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 | 0,003 | 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 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,003 |
| 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 ».