Abstract 2259: Novel metallotherapeutic BOLD-100 induces circulating cytokine changes when administered in combination with FOLFOX in advanced gastrointestinal cancer patients
Notice bibliographique
Résumé
Abstract Proven metallotherapeutics, such as cisplatin and oxaliplatin, alter immune responses as part of their multimodal mechanisms-of-action. These immune responses can drive efficacy in specific patient populations and/or in combination with other oncology drugs. BOLD-100, currently in a multinational Phase 2 trial, is a first-in-class metallotherapeutic that (1) alters the unfolded protein response (UPR) through selective GRP78 inhibition, and (2) induces reactive oxygen species (ROS), leading to DNA damage and cell cycle arrest. Collectively, these pathways result in cell death in both sensitive and resistant cancers, giving BOLD-100 the potential to significantly improve outcomes in a wide range of both solid and liquid tumors in combination with other anticancer therapies. BOLD-100 can also alter immune responses, including through induction of immunogenic cell death, but these responses have not been investigated in a clinical population. A recently completed Phase 1b trial investigating BOLD-100 in combination with FOLFOX demonstrated a 3X improvement in progression-free survival (PFS) in 3rd line or later metastatic colorectal cancer patients compared to existing therapies, with a favorable safety profile. In this Phase 1b study, BOLD-100 was administered via IV infusion for 60-90 minutes immediately prior to FOLFOX on a 2-week cycle. To investigate the pharmacodynamics of immune markers, plasma samples were collected at baseline and 1, 6, 24, and 48 hours after initiation of BOLD-100 plus FOLFOX treatment for each of the first 4 cycles, and then at baseline for all subsequent cycles. In 326 samples collected from 15 patients, 48 cytokines were measured via multiplex. Multiple cytokines showed short-term (1 to 48 hours) transient increases in plasma concentration levels, including IL-10, IL-27, G-CSF, MIP-1β, IP-10, IL-2, IL-18 and TNFα. IL-10, a cytokine previously investigated as an anticancer therapeutic, increased significantly by 1 hour (6.7X increase) and by 6 hours (84.5X increase) after treatment, before reverting to baseline levels by 48 hours. Despite large acute increases in specific cytokines, no changes to baseline levels over multiple treatment cycles were observed. Correlation analysis showed that baseline MCP-1 and MIP-1α levels were negatively correlated with overall survival; and the maximum change in concentration over the first dosage cycle of RANTES, IL-17F, Eotaxin, TGFα and MDC were positively correlated with overall survival. These results show that BOLD-100 in combination with FOLFOX can induce immune responses, and that these immune responses may predict clinical outcome. Analysis of additional patient samples from the Phase 2 trial is ongoing. Citation Format: Mark Bazett, Brian Park, E Russell McAllister, Jim Pankovich. Novel metallotherapeutic BOLD-100 induces circulating cytokine changes when administered in combination with FOLFOX in advanced gastrointestinal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2259.
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 machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| 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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 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 source (Gemma direct ou Codex distillé), 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 ».