415. The Potency of a Histone Deacetylase Inhibitor and Reolysin in Head and Neck Squamous Cell Carcinoma
Notice bibliographique
Résumé
Introduction: There is a clear and pressing need for novel therapies with activity against locally advanced head and neck cancers which still carry a dismal prognosis. Oncolytic viruses are powerful, targeted anti-cancer agents. Reovirus is a naturally occurring non-pathogenic virus that was isolated from the human respiratory and gastrointestinal tracts. Moreover, Reovirus type 3 Dearing (Reolysin; Oncolytics Biotech Inc., Calgary, AB, Canada) is currently being tested in phase I-III clinical trials in a variety of tumor types. Histone deacetylase inhibitors (HDACi) comprise a structurally diverse class of compounds that are targeted anticancer agents. The first FDA approved HDACi, vorinostat (suberoylanilide hydroxamic acid-SAHA), is highly effective in the treatment of cutaneous Tcell lymphoma. SAHA is currently being testing in head and neck cancer clinical trials. We previously found a synergistic combination of SAHA and Reolysin in a nude mouse model. Preclinical models of oncolytics are often in immunocompromised mice, negating the significant impact of the immune system. Mounting evidence demonstrates that the immune system is critically important in oncolytic viral response. In this study, we sought to investigate the impact of this combination in an immunocompetent model. Methods: Cell survival experiments were performed with reovirus and SAHA in shPTP-BL-Ras SCC cells. IC50 values were interpolated from a sigmoidal dose-response curve fit of the log-transformed survival data. JAM-1 surface levels were assessed via flow cytometric analysis. Cells were collected after 48 hours and cell death was assessed via Annexin V and PI staining. JAM-1 levels were assessed using anti-JAM-1-PE staining as compared to a control isotype-PE antibody. Whole splenocytes were isolated at the time of death for C57BL/6 mice bearing MTE tumors treated in 4 groups (control, SAHA, reovirus, and combination). Three independent mice were stained per group for the following: B cells (CD19+), NK cells (CD49b+), activated NK cells (CD49b+NKp46+), dendritic cells (CD11c+) and activated DCs (CD11c+MHCII+ or CD11c+CD86+), CD4 T helper (CD3+CD4+), and CD8 cytotoxic cells (CD3+CD8+). Results: Experiments demonstrated significant efficacy of SAHA and Reolysin treatment in vitro and in the immunocompetent mouse model. Combination therapy exhibited a synergistic anti-tumor effect with a significant increased survival of mice compared to any of the agents alone. The Jam1 receptor was upregulated on tumor cells allowing enhanced reovirus uptake. There was marked and significant reduction in circulating B cells in combination treated mice versus all other groups. Activated NK cells were decreased in the combination group. T cells and dendritic cells (CD11c+MHCII+) were reduced in the SAHA groups. SAHA model withdrawal experiments show a significant synergistic response and immune system rebound after SAHA cessation. Conclusion: This data demonstrates that combination of reovirus plus SAHA therapy has significant activity in the treatment of SCCHN, even in an immunocompetent model. Immune inhibition due to SAHA as well as increased Jam1 receptor expression on tumor cells results in a synergistic effect of the combination therapy. Immune system rebound likely plays a significant role in the long-term anti-tumor response. This strong preclinical evidence supports the translation of this combination to phase-I clinical trials.
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 ».