400 Preclinical characterization and modelling of allogeneic Vγ9Vδ2 TAC T cells for the treatment of solid tumors
Notice bibliographique
Résumé
<h3>Background</h3> The T cell antigen coupler (TAC) is a novel, proprietary chimeric receptor that facilitates the redirection of T cells to tumor cells and activates T cells by co-opting the endogenous T cell receptor complex with the goal to elicit safe and durable anti-tumor responses. TAC01-HER2, a first-in-class, autologous TAC T cell product targeting HER2 (ERBB2), has entered a phase I/II clinical trial in patients with HER2-positive solid tumors. Vγ9Vδ2 (γδ) T cells belong to a subset of T cells that recognize target cells independent of human leukocyte antigen (HLA). Consequently, γδ T cells do not cause graft-versus-host (GvH) disease and thus, have the potential for allogeneic cell therapy applications. Here, we present preclinical data of an allogeneic HER2-TAC product based on Vγ9Vδ2 T cells. <h3>Methods</h3> The potency and safety of HER2-TAC γδ T cells generated from multiple donors was evaluated using various <i>in vitro</i> and <i>in vivo</i> assays. Flow cytometric analysis was used to determine cellular phenotypes, intracellular cytokines, CD69 upregulation, and T cell proliferation in response to target antigen. Cytotoxicity was assessed via both luciferase-based killing and real-time microscopy-based co-culture assays. To assess HER2-TAC γδ T cell responses to HLA mismatches between unrelated donors, mixed lymphocyte reactions (MLR) were performed using dendritic cells representing the major North American HLA subtypes. <i>In vivo</i> studies examined the anti-tumor effects of HER2-TAC γδ T cells against established HER2-expressing solid tumors. <h3>Results</h3> HER2-TAC γδ T cells selectively reacted to HER2-expressing tumor cells<i> in vitro</i>, as measured by CD69 upregulation, intracellular cytokine production, proliferation, and cytotoxicity. In contrast, HER2-TAC γδ T cells failed to show proliferative activity in MLR assays, indicating that HER2-TAC γδ T cells are likely free of GvH reactivity. In addition, HER2-TAC γδ T cells showed strong anti-tumor efficacy in HER2-positive tumor xenograft models without signs of toxicity. Similar anti-tumor efficacy was observed in both NSG mice bearing the human IL-15 transgene (Tg-hIL-15) and NSG mice supplemented with exogenous IL-15. Comparison of serum IL-15 levels between Tg-hIL15 mice and NSG mice with cytokine supplementation revealed significantly lower levels in Tg-hIL15 mice, suggesting that Tg-hIL15 mice may be a more physiologically relevant model to study γδ T cells <i>in vivo</i>. <h3>Conclusions</h3> HER2-targeted TAC γδ T cells display strong and specific activity against HER2-expressing tumor models <i>in vitro</i> and <i>in vivo.</i> This highlights the versatility of the TAC platform and its potential in the development of an allogeneic product for therapeutic applications in solid tumors. <h3>Ethics Approval</h3> Animal studies performed for the work presented in this abstract were conducted under the Animal Utilization Protocol (AUP) # 20–10-37 and approved by the Animal Research Ethics Committee at McMaster University (Hamilton, ON, Canada).
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 distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
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 tête enseignante, 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 ».