865 Combining radiotherapy with novel TLR-based immunotherapy for improved tumor control in lung cancer
Notice bibliographique
Résumé
<h3>Background</h3> STING agonists have become an attractive immunomodulatory approach to activate the cGAS-STING pathway for turning cold tumors hot and thereby improving the efficacy of Immune Checkpoint Inhibitors (ICI). However, considering their modest clinical efficacy, there is a substantial need for other approaches to activating the cGAS-STING pathway for cancer immunotherapy. Inhibition of the enzyme ENPP1, a negative regulator of the cGAS-STING pathway is one such approach. ENPP1 hydrolyses 2′3′- cGAMP (endogenous STING agonist) and negatively regulates STING dependent immune activation. Several tumors like human astrocyte tumors and TNBC like 4T1 and MDA-MB-231 have high ENPP1 expression which plays a key role in tumor progression and blocks T cell infiltration. ENPP1 not only abolishes the cGAS-STING mediated immune activation but also produces adenosine, an immune suppressor which promotes cell migration. AVA-NP-695 is a highly potent orally available small molecule ENPP1 inhibitor being developed for cancer immunotherapy. <h3>Methods</h3> Inhibition potencies of AVA-NP-695 were confirmed by enzymatic assays using substrates like <i>p</i>-Nitrophenyl-5′-TMP, 2’3’-cGAMP and ATP. The efficacy of AVA-NP-695 was demonstrated in 4T1 Tumor bearing BALB/c mice as monotherapy and in combination with anti-PD-L1, Olaparib and Paclitaxel. Efficacy of AVA-NP-695 in combination with radiation was also evaluated in ENPP1 overexpressing breast tumors. Finally, combination of PSMA-RLT with AVA-NP-695 was evaluated for treating prostate cancer. <h3>Results</h3> We demonstrate that AVA-NP-695, a selective and potent small molecule ENPP1 inhibitor showed no adverse effects at 1000 mg/kg BID in 14 day repeated dose toxicity in BALB/c mice, thereby demonstrating an excellent therapeutic window. Results from <i>in-vivo</i> studies have shown superior tumor growth inhibition (TGI) and impact on metastasis by AVA-NP-695 (6 mg/kg BID) compared to Olaparib and Anti-PD1 in a syngeneic 4T1 breast cancer mouse model. Subsequently, combination of AVA-NP-695 with Anti-PDL1, Olaparib and Paclitaxel demonstrated encouraging combinatorial efficacy of AVA-NP-695 along with Paclitaxel. Monotherapeutic arm for Paclitaxel and AVA-NP-695 depicted 40% and 44% TGI respectively; however their combined treatment resulted in ~60% TGI. Additionally, the AVA-NP-695 treatment alone showed 50% enhanced mean survival time followed by 68%, 68% and 72% when given in combination with anti-PD-L1, Olaparib and Paclitaxel respectively. Finally, combination of AVA-NP-695 with radiation (Fractionated dose and Targeted Radionuclide) demonstrated substantial tumor growth reduction across various tumor models. <h3>Conclusions</h3> The potent anti-tumor efficacy of AVA-NP-695 both as monotherapy and combination along with its safety profile provides a strong rationale for the therapeutic potential of AVA-NP-695 against solids tumors, particularly breast cancer. <h3>Ethics Approval</h3> All animal studies involved obtained the prerequisite ethics committee(s) approval.
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 | 0,001 | 0,000 |
| 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 | 0,000 |
| 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 ».