Abstract 2709: TTI-622 (SIRPα-IgG4 Fc), a CD47-blocking innate immune checkpoint inhibitor, suppresses tumor growth and demonstrates enhanced efficacy in combination with antitumor antibodies in both hematologic and solid tumor models
Notice bibliographique
Résumé
Abstract Tumor cells frequently evade macrophage-mediated destruction by increasing cell surface expression of CD47, which delivers an anti-phagocytic (“do-not-eat”) signal by binding the inhibitory signal regulatory protein α (SIRPα) receptor on macrophages. Previous studies have shown that blockade of the CD47-SIRPα pathway using TTI-621, a soluble SIRPα-IgG1 Fc fusion protein, triggers macrophage phagocytosis of tumor cells in vitro, and potently inhibits tumor growth in vivo. In the current study, the in vitro and in vivo efficacy of TTI-622, a soluble SIRPα-Fc variant protein containing an IgG4 Fc tail, was evaluated in multiple model systems. Unlike CD47-blocking antibodies, TTI-622 binds minimally to human erythrocytes, and does not induce hemagglutination in vitro. Therefore, it avoids a large circulating antigen sink, and is less likely to cause anemia in patients. Additionally, TTI-622 potently induces phagocytosis of a broad panel of tumor cells derived from patients with both hematological and solid tumors. Although in vitro phagocytosis of human platelets is also observed, TTI-622 preferentially induces phagocytosis of tumor cells over platelets in a competitive phagocytosis assay. The in vivo efficacy of TTI-622 monotherapy and/or combination therapy was evaluated in different tumor models. In a DLBCL (Toledo) xenograft tumor model, both early and delayed treatments resulted in statistically significant decreases in tumor growth, and improved survival relative to treatment with control Fc. In the Burkitt lymphoma (Daudi) and multiple myeloma (MM.1S) xenograft tumor models, the potential of combining TTI-622 with daratumumab (anti-CD38 antibody) was also explored. In both models, TTI-622 monotherapy demonstrated partial tumor growth inhibition. However, the therapeutic efficacy was further enhanced when TTI-622 was combined with daratumumab. Intriguingly, a TTI-622 non-responsive head and neck cancer (FaDu) xenograft tumor model became responsive by combining TTI-622 with suboptimal doses of cetuximab (anti-EGFR antibody). The combination of TTI-622 with cetuximab resulted in a statistically significant decrease in tumor growth, and improved survival relative to monotherapy treatments. Collectively, these results demonstrate that TTI-622 induces potent, tumor-specific macrophage phagocytosis across a range of hematological and solid tumors, and is efficacious as a monotherapy agent in a DLBCL xenograft tumor model. Furthermore, TTI-622 potentiates the efficacy of daratumumab and cetuximab in hematological and solid xenograft tumor models, respectively. These data support the clinical evaluation of TTI-622 in combination with anti-tumor antibodies in cancer patients with both solid and hematological malignancies. Citation Format: Gloria H. Y. Lin, Natasja N. Viller, Marilyse Chabonneau, Laura Brinen, Tapfuma Mutukura, Karen Dodge, Simone Helke, Vien Chai, Violetta House, Vivian Lee, Hui Chen, Alison O'Connor, Debbie Jin, Rene Figueredo, Saman Maleki Vareki, Mark Wong, Emma Linderoth, Lisa D. Johnson, Xinli Pang, James Koropatnick, Jeff Winston, Penka S. Petrova, Robert A. Uger. TTI-622 (SIRPα-IgG4 Fc), a CD47-blocking innate immune checkpoint inhibitor, suppresses tumor growth and demonstrates enhanced efficacy in combination with antitumor antibodies in both hematologic and solid tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2709.
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 | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,000 | 0,001 |
| 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 ».