Abstract PO-093: Crenolanib improves PD-1 response and overall survival in immune checkpoint inhibitor resistant murine models of oral squamous cell carcinoma
Notice bibliographique
Résumé
Abstract Background: Present line indications for pembrolizumab are for patients with metastatic or unresectable recurrent (i.e. incurable) head and neck squamous cell carcinoma (HNSCC). However, only a minority of patients on immunotherapy will realize a durable survival benefit because >80% of patients with metastatic HNSCC do not respond to PD-1 blockade. Tumor microenvironment mesenchymal stem cells (MSCs) and cancer associated fibroblasts (CAFs) have been reported significantly contribute to chemotherapy and radiation resistance. Moreover, MSCs have been shown to contribute to an immunosuppressive tumor microenvironment by upregulating PD-L1 in breast cancer models. We have previously shown crenolanib improves MSC mediated cisplatin resistance in vitro through modulation of MSC-mediated activation of AKT signaling, therefore we hypothesize that targeting MSCs may be of therapeutic benefit alone and in combination with anti-PD1 immunotherapy. Methods: Oral cancer was induced in the buccal space of C56/BL6 mice with the murine oral cancer cell lines MOC1 or PD-1 resistant cell line, MOC2. When tumors reached approximately 5 × 5 mm, mice were treated with 15 mg/kg (low dose) or 30 mg/kg crenolanib (high dose) for five consecutive days over 3 weeks. Tissue were harvested for immunohistochemistry and immunofluorescence analysis and ex vivo cell cultures prepared for analysis by western immunoblotting and flow cytometry. Results: There was a significant reduction in tumor volume in mice bearing MOC1 and MOC2 tumors (p<0.03) treated with either low or high dose crenolanib compared to vehicle control. Overall survival was also significantly improved in mice bearing MOC1 tumors treated with high dose crenolanib compared to mice treated with vehicle control (p<0.04) and approached significance in MOC2 mice treated with low dose crenolanib. Tumor sections were imaged by immunofluorescence microscopy. There was a decrease in expression of PDGFR-α on MOC1 tumor cells and α-SMA on tumor microenvironment stromal cells in mice treated with crenolanib compared to vehicle control, suggesting crenolanib targets both cell types. There was a significant reduction in tumor volume (p<0.0001) and improved overall survival (p<0.0004) in mice bearing MOC2 tumors treated with combination crenolanib plus pembrolizumab compared to vehicle plus pembrolizumab. Conclusions: Preliminary in vivo data suggests crenolanib may be efficacious when used in combination with anti-PD1 immunotherapy by inhibiting the immunosuppressive effects of tumor microenvironment MSCs. Citation Format: Xiangfeng Shen, Katherine Gonzalez, Rico Castillo, Ashlyn Rickard, Yvonne Mowery, Tammara Watts. Crenolanib improves PD-1 response and overall survival in immune checkpoint inhibitor resistant murine models of oral squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-093.
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 | 0,006 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| 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 | 0,001 |
| 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 ».