Characterization of CD20 expression loss as a mechanism of resistance to mosunetuzumab in patients with relapsed/refractory B-cell non-Hodgkin lymphomas.
Notice bibliographique
Résumé
7526 Background: Mosunetuzumab (M) is a bispecific antibody targeting CD20 and CD3 that redirects T cells to engage and eliminate malignant B cells being developed for relapsed or refractory (R/R) B-cell non-Hodgkin lymphomas (B-NHL). CD20 is an optimal target, with uniform expression across B-NHL histologies and minimal receptor turnover. We characterized CD20 loss as a potential mechanism of resistance to M in patients (pts) on a Phase I/II trial (NCT02500407) receiving M monotherapy for the treatment (tx) of R/R B-NHL. Methods: Pts with R/R B-NHL received M intravenously in 3-week cycles, for eight to 17 cycles depending on tumor response. At baseline (BL), biomarker-evaluable (archival or fresh) biopsies were collected from 293 pts. Biopsies from 62 pts were collected at additional time points during tx with M and/or at disease progression (PD). The proportion of CD20+ and PAX5+ tumor cells was determined by immunohistochemistry (IHC) using dual-staining with anti-CD20 (clone L26, VENTANA) and anti-PAX5 (clone DAK-PAX5, DAKO) antibodies. Expression of MS4A1, the gene encoding CD20 , was measured by RNA-sequencing (RNA-seq); MS4A1 mutation profiling was performed by whole exome sequencing (WES). Levels of CD20 expression were assessed relative to response rates. Correlative analyses were performed and assessed centrally (IHC, RNA-seq, and WES) and locally (IHC). Results: CD20 levels were consistently high ( > 75% CD20+PAX5+ cells) in the majority of BL biopsies and generally comparable across histologies (FL, DLBCL, tFL, MCL, and RT). BL CD20 loss (≤5% CD20+PAX5+ cells) was seen in 16/293 pts (5.5%), more commonly in aggressive NHL, and responses to M were not seen in these pts. Among 62 pts with BL and on-tx/at-PD biopsies, BL CD20 levels were ≤5% in 7/62 pts (11%) (6/7 pts [86%] progressed before completing Cycle 2). CD20 levels were maintained in on-tx biopsies from 23/24 pts (96%). At PD, biopsies showed CD20 loss in 7/26 pts (27%). For five pts with BL, on-tx and at-PD biopsies, all pts maintained CD20 while on-tx and 1/5 pts (20%) had CD20 loss at PD. There was no clear association between CD20 reduction and histology. Data from 185 BL biopsies showed generally concordant levels of CD20 gene and protein expression (r = 0.72). In 10/185 pts (5%), MS4A1 was expressed without detectable CD20 protein expression; DNA sequencing revealed novel mutations in MS4A1, including mutations leading to truncation of the protein. CD20 transmembrane and extra-cellular domain mutations were also observed but do not block CD20 expression. Conclusions: In pts with R/R B-NHL treated with M, low BL CD20 expression is associated with lack of response to M. During M tx, loss of tumor cell expression of CD20 is one mechanism of acquired resistance; however, CD20 expression is maintained in most pts with PD, implying alternative mechanisms for acquired M resistance. Clinical trial information: NCT02500407.
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 ».