Correlative and spatial transcriptomic analysis of olaparib and durvalumab in patients with recurrent/refractory <i>IDH</i> -mutant gliomas.
Notice bibliographique
Résumé
2075 Background: Combination of immune checkpoint and PARP inhibition has potential synergistic effects in IDH mt gliomas in pre-clinical models. Durvalumab and olaparib demonstrated objective responses in a subset of patients (pts) with IDH mt gliomas (NCT03991832). We report mutational, transcriptomic, and spatial correlative analysis of pts samples from baseline and at time of progression. Methods: Pts with recurrent/refractory IDH mt gliomas received olaparib 300 mg twice daily and durvalumab 1500 mg IV every 4 weeks until disease progression as determined by RANO 2.0 criteria. Whole exome sequencing (WES, n = 28) and total RNA sequencing (RNA-seq, n = 21) were performed on baseline archival formalin-fixed, paraffin-embedded tumor samples. Baseline tumor microenvironment was characterized with multiplex-immunohistochemistry (n = 29). Matched responders (n = 4) and non-responders (n = 6) were further profiled using 10X Visium HD for spatial transcriptomics. An unsupervised deconvolution method was applied using consensus non-negative matrix factorization for de novo discovery of expression programs corresponding to cell types and cell states. Associations with objective response (OR) to therapy were determined using either Fisher’s exact test or rank-sum test. Results: In the 29 pts enrolled between January 2020–February 2023, median age was 40.5 (range 23–66) and 41% were female. The initial tumor grade was 2 (n = 9), 3 (n = 8), and 4 (n = 12). The OR rate was 14% (95% CI 3.9–32%), 1 complete response and 3 partial responses. All cases were mismatch repair proficient. The median tumor mutation burden (TMB) was 16.5, with TMB > 10 in 21 pts (75%). Baseline TMB was not associated with response. The most common co-mutations were TP53 (n = 21, 75%), ATRX (n = 20, 71%), ARID1A (n = 7, 25%), CIC (n = 4, 14%), and NF1 (n = 3, 11%), none were associated with response. There were no canonical mutations in BRCA1 , BRCA2 , or PALB2 . Pathway analysis on differentially expressed genes between responders and non-responders showed convergence on interferon signaling and inflammation among responders (p < 0.001). Lower pre-existing M2-polarized tumor associated macrophages/microglia (high expression of CD68, PDL1, CD163) was associated with response (p < 0.01). These findings were supported by metaprograms in the HD spatial data, which showed higher levels of CD8+ cytotoxic T-cells at baseline in responders. Conversely, M2-polarized macrophage/microglia were enriched in non-responders. Paired progression samples will additionally be presented. Conclusions: Responders to olaparib and durvalumab had decreased baseline M2-polarized macrophages/microglia and increased pre-existing immunogenicity (interferon signaling). Several spatially conserved expression metaprograms targeting baseline immune infiltration were associated with response. Clinical trial information: NCT03991832 .
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 | 0,000 |
| 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 ».