544 Coordinated blockade of TGF-β and PD-L1 by bintrafusp alfa promotes survival in preclinical ovarian cancer models by promoting T effector memory responses
Notice bibliographique
Résumé
<h3>Background</h3> Ovarian cancer is a leading cause of mortality in women due to late detection and lack of durable therapy responses. The most aggressive subtype is high grade serous ovarian cancer (HGSC). Within the ascites, high levels of the immunosuppressive cytokine Transforming Growth Factor-β (TGF-β) is linked to poor prognosis. We hypothesize that aberrant TGF-β signaling in the tumor microenvironment promotes resistance to immunotherapies, including immune checkpoint inhibitors targeting PD-1/PD-L1. Here, we test whether dual blockade of TGF-β and PD-L1 with bintrafusp alfa provokes durable anti-tumor immune responses in preclinical HGSC models. <h3>Methods</h3> Two murine HGSC syngeneic engraftment models were used to model advanced metastatic HGSC. Mouse ID8-Trp53<sup>-/-</sup>/Brca2<sup>-/-</sup>-Luc HGSC cells were injected intraperitoneally into female B cell-deficient μMT<sup>-</sup> mice (C57BL/6 background). Control IgG or bintrafusp alfa treatments were administered twice weekly, and HGSC was monitored using IVIS. Treatment effects on survival, tumor burden, ascites volume, cytokines, and immunophenotypes were compared. Mouse BR5-Luc (Trp53<sup>-/-</sup>/Brca1<sup>-/-</sup>;Myc<sup>O/E</sup>/Akt<sup>O/E</sup>) HGSC cells were engrafted into female FVB mice. During control IgG or bintrafusp alfa treatments, B cells were depleted using anti-CD20 injections every 3 weeks to avoid neutralization of the humanized proteins. Survivor mice were rechallenged to test memory responses and immunophenotypes compared to naïve FVB control mice. A simplified co-culture model of HGSC killing by cytotoxic T cells was established using T cells from OT-1 transgenic mice and BR5-Luc cells transduced with chicken ovalbumin antigen and a Granzyme B-cleavable FRET reporter. <h3>Results</h3> In the ID8 syngeneic HGSC model, bintrafusp alfa treatments reduced ascites development and HGSC tumor burden. Analysis of the ascites revealed depletion of TGF-β and VEGF, with increased CD8 T cell activation and M1 tumor-associated macrophages. In the BR5 syngeneic model, bintrafusp alfa treatments led to HGSC rejection and ∼ 50% survivors. Upon rechallenge, 75% of survivor mice were protected from HGSC without further treatments. These mice had increased peritoneal CD4 and CD8 T effector memory cells and NK cells compared to naïve mice. Testing bintrafusp alfa in an HGSC/T cell co-culture model, we found increased expression of Granzyme B and improved Granzyme B-mediated killing of BR5-Luc cells compared to controls. Bintrafusp alfa also reduced the HGSC-targeting integrin CD103 compared to controls. <h3>Conclusions</h3> These results show that coordinated blockade of TGF-β and PD-L1 by bintrafusp alfa leads to acquired anti-tumor immunity in HGSC models. Since bintrafusp alfa has advanced to clinical trials in other cancers, this project has potential to inform new immunotherapy regimes for ovarian cancer patients. <h3>Acknowledgements</h3> We acknowledge funding and in-kind contributions from CIHR and EMD Serono.
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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 | 0,002 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| 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 ».