Abstract 1761: Combination of a T cell activating immunotherapy with immune modulators alters the tumor microenvironment and promotes more effective tumor control in preclinical models
Notice bibliographique
Résumé
Abstract Combinations of immune therapies for cancer treatment will likely improve clinical responses, and a treatment that stimulates a robust T cell response may be a key component of therapy in patients with poorly infiltrated tumors. DPX-Survivac is a T cell activating therapy targeting survivin, formulated in DepoVax™ (DPX), an oil based delivery platform. In clinical studies, the MHC class I peptide antigens in DPX-Survivac induced strong and sustained T cell responses when used in combination with metronomic cyclophosphamide (mCPA) in ovarian cancer patients. Epacadostat is an indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor which has shown to reduce immune suppression in tumors and has demonstrated encouraging results in clinical trials. Using preclinical mouse tumor models, we evaluated the combination of these three immune therapies. C57Bl/6 mice were implanted subcutaneously with murine pancreatic adenocarcinoma (Panc02) cells. Groups of mice were vaccinated with DPX-Survivac vaccine (containing murine H2D peptides) by subcutaneous injection and treated with mCPA (20 mg/kg/day, PO) and epacadostat (6 mg/day, PO). The combination of the three treatments provided a significant delay in tumor progression, and improvement in survival over untreated animals. Similar findings were also observed in the HPV16 E7 expressing C3 tumor model, using an HPV16 minimal peptide epitope (HPV16 E749-57) formulated in DPX. In this model, mice were terminated at defined endpoints to evaluate systemic immune responses in the spleen by IFN-γ ELISPOT and profile tumor infiltration by flow cytometric analysis. Although antigen-specific immune responses in the spleen were not increased by the triple combination in comparison to the DPX-based vaccine, there was a significant impact on several immune subtypes found in the tumor. Notably, antigen-specific CD8+ T cells (as detected by dextramer analysis) were increased and regulatory CD4+CD25+FoxP3+ T cells (Tregs) were decreased. In comparison, the Treg population in the spleen was highest in the triple therapy group (p=0.0046 compared to DPX/mCPA alone). This may indicate a selective exclusion of Tregs from the tumor microenvironment is induced by epacadostat, which can facilitate the anti-tumor immune response mediated by CD8+ T cells induced by DPX. Other immune modulating therapies, such as anti-PD-L1, may further enhance the tumor control induced by this treatment. The combination of DPX-based, T cell activating therapy with epacadostat, a drug that reduced tumor immune suppression is a rational, synergistic combination that is currently being evaluated in advanced ovarian cancer patients in the DeCidE1 clinical trial (NCT0278520). Citation Format: Alecia MacKay, Genevieve Weir, Holly Koblish, Ava Vila- Leahey, Valarmathy Kaliaperumal, Cynthia Tram, Peggy Scherle, Marianne Stanford. Combination of a T cell activating immunotherapy with immune modulators alters the tumor microenvironment and promotes more effective tumor control in preclinical 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 1761.
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) | 0,001 | 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 | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 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 ».