1396 TriTCE CPI: a novel trispecifc T cell engager platform with integrated PD-1/PD-L1 checkpoint inhibition engineered for the treatment of immunosuppressed tumors
Notice bibliographique
Résumé
<h3>Background</h3> Immunosuppression in the solid tumor microenvironment (TME) is a critical obstacle that has limited the efficacy of T cell engager (TCE) immunotherapies. Though TCEs can direct T cell cytotoxicity towards tumors, T cell activation and inflammation can induce tumor cell and T cell expression of immune checkpoint proteins, such as PD-L1. This treatment-related increase in immune suppression in the TME further limits clinical responses. We have previously presented screening data on a panel of trispecific T cell engagers (TriTCEs). Preliminary mechanistic data showed enhanced antitumor activity where TriTCEs can concurrently direct T cell activity towards tumor cells while eliciting PD-1/PD-L1 checkpoint inhibition (CPI) by the addition of an affinity-engineered PD-1 domain to the TCE. Here, we present data that further characterizes and differentiates the lead TriTCE CPI formats. <h3>Methods</h3> Lead TriTCE CPI formats were screened for potency <i>in vitro</i>. Co-engagement of CD3, tumor-associated antigen (TAA), and PD-L1 by TriTCE CPIs was determined using on-cell binding measurements to exhausted T cells and tumor cells stimulated with IFNγ to upregulate PD-L1 and recapitulate cellular phenotypes expected to be found in an immunosuppressed TME. TriTCE CPI mediated T cell activation in the presence of PD-L1 expressing dendritic cells was assayed in co-culture. <i>In vivo</i> activity was determined using humanized PBMC and syngeneic mouse models. <h3>Results</h3> Lead TriTCE CPI formats were compared by assaying TAA-dependent cytotoxicity where addition of affinity-engineered PD-1 increased potency <i>in vitro</i>. Format-dependent differences in PD-1 location on the TriTCE and the presence of one or two α-TAA binding arms was found to enhance avidity-driven binding, which translated into increased T cell-dependent cytotoxicity compared to clinical benchmark controls. Lead TriTCE CPIs had broad anti-tumor activity across tumor cell lines with varying TAA and PD-L1 expression levels. <i>In vivo</i> testing of lead TriTCE CPI formats demonstrated tumor growth inhibition and enabled preliminary assessment of toxicity. A threshold for tolerability of affinity-engineered PD-1 was identified in humanized syngeneic mouse model. <h3>Conclusions</h3> Our next-generation TriTCE CPIs aim to leverage PD-L1-mediated immunosuppression for enhanced avidity-driven tumor cell targeting and CPI in the TME to improve T cell responses in solid tumors. Addition of an affinity-engineered PD-1 to the TCE enhanced activity across multiple tumor cell lines compared to a bispecific TCE, supporting that TriTCE CPIs can be active against primary and acquired PD-L1 resistance mechanisms. Humanized immunocompetent syngeneic mouse models suggest a widened therapeutic window based on measures of tumor regression with a favorable safety profile. <h3>Ethics Approval</h3> The protocol and procedures involving the care and use of animals in these studies was conducted in accordance with the regulations of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) and were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC; CrownBio, Jackson ImmunoResearch).
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 | 0,001 |
| 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 ».