Abstract CT176: Pharmacokinetic/pharmacodynamic (PK/PD) relationships of the novel Treg depleter RG6292 in Phase Ia and Ib studies in patients with solid tumors
Notice bibliographique
Résumé
Abstract INTRODUCTION: Activated Tregs in the tumor micro-environment are correlated with poor outcomes, and are considered as key players in tumor immune-escape. So far, Treg depletion has not been successful in patients, either because adequate Treg depletion was not achieved or because Teff cells have either been impacted or depleted as well. RG6292 is the first anti-human CD25 antibody developed to specifically deplete human Tregs while preserving IL-2R STAT5 signaling and Teff activity. It has been optimized for ADCC and selective depletion of cells with high CD25 density (Treg). MATERIALS and METHODS: Adult patients with advanced solid tumors were given RG6292 i.v. Q3W as monotherapy (S1: NCT04158583) or in combination with atezolizumab 1200 mg Q3W (S2: NCT04642365) in a Ph1 dose escalation study. 76 pts have been treated at dose levels ranging from 0.3 mg to 165 mg in S1 and 48 pts at dose levels ranging from 0.3 mg to 160 mg in S2. In both studies a Bayesian logistic regression model with overdose control guided dose escalation was utilized. Data cutoff was May 27, 2022. Pharmacokinetic and pharmacodynamic analyses were undertaken in peripheral blood and tumor tissue. PK/PD modeling applied to Treg and Teff cells helped characterize and identify the optimal therapeutic window to ensure (1) relevant Treg depletion and (2) limited impact on T effector. RESULTS: RG6292 has a linear and time independent PK with no ADA detected. A Population PK-PD modeling approach was applied to Treg and Teff cells in the periphery. To predict the RG6292 effects in the tumor microenvironment (TME), the PK/PD relationships observed and characterized in the periphery for all cell subpopulations were considered the same, a tumor uptake factor of 15% was considered. At steady-state trough, a 70 mg Q3W dose was predicted to lead to 72% of patients with concentration above the Treg (%CD4) EC50 in tumor and 40% of patients with concentration above the Non-Treg (%CD4) EC50 in plasma. RG6292 induced a dose-dependent peripheral and intratumoral Treg depletion in on-treatment biopsies taken 28 days after initiation of treatment. Treatment did not appear to impact the number nor the functionality of intratumoral CD8 T cells nor any evident effect observed on PDL1 expression. In blood, stable levels of all other immune cells were observed after treatment. Moreover, in both studies a marginal increase of IFNg, CXCL10, IL-10, TNF was observed. No consistent gene expression alterations nor immune signatures could be observed when comparing BSL vs OT biopsies in S1. CONCLUSION: RG6292, consistent with its proposed mechanism of action, induces profound and preferential depletion of Treg cells over CD8+CD25+ in the periphery and in the TME at clinically safe doses between 35-70mg. Further development of RG6292 is currently being explored. Citation Format: Tamara Tanos, Kevin Smart, Valentina Gambardella, Kristoffer Rohrberg, Michael Ong, Maria Esperanza Rodriguez Ruiz, Jean-Pascal Machiels, Miguel Fernández Sanmamed, Josep Tabernero, Anna Spreafico, Daniel Renouf, Stephen Luen, Rachel Galot, Bernard Doger, Emiliano Calvo, Aung Naing, Samira Curdt, Nicolas Staedler, Mike Flores, Enrique Gómez Alcaide, Chiahuey Ooi, Michael Hettich, Sebastian Dziadek, Yuying Xie, Gabriel Schnetzler, Theresa Kolben, Linxinyu Xu, Vaios Karanikas, Christophe Boetsch. Pharmacokinetic/pharmacodynamic (PK/PD) relationships of the novel Treg depleter RG6292 in Phase Ia and Ib studies in patients with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT176.
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 | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,001 |
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 ».