Intensity of Survivin Expression Correlates with Clinical and Biological Markers of Aggressive R/R DLBCL
Notice bibliographique
Résumé
Introduction: The SPiReL phase II clinical trial evaluated combination immunotherapy with an immunogenic vaccine formulation to the tumor antigen survivin comprised of maveropepimut-S (MVP-S), pembrolizumab and cyclophosphamide in survivin-expressing relapsed or refractory (R/R) diffuse large B cell lymphoma (DLBCL). The efficacy of this survivin-directed T cell educating therapy may be influenced by the survivin antigen burden in the DLBCL. To further explore this potential relationship, we evaluated the heterogeneity of tumor survivin expression in the SPiReL study cohort and its associations with established clinical-pathological DLBLC variables. Methods: Survivin immunohistochemistry (IHC) was performed at NeoGenomics Laboratories (Aliso Viejo, California, USA) on formalin fixed paraffin embedded (FFPE) tumor slides from diagnostic biopsies obtained at trial screening. Inclusion criteria stipulated >10% of tumor cells expressing survivin by IHC. Semi-quantitative survivin expression metrics, as determined by pathologist assessment, included: total percentage of survivin-positive cells; intensity of survivin staining scored as 0 = None, 1+ = Weak, 2+ = Moderate, 3+ = Strong; and H-score, a linear weighted average (% positive cells x staining intensity level). Radiologic tumor burden was measured at up to 4 time points during the trial by computed tomography (CT). Other pathology (e.g. cell of origin) and laboratory biomarkers (e.g. lactate dehydrogenase, LDH) were extracted from clinical results. Results: The mean and median percentage of survivin-positive tumor cells for all enrolled participants (n= 25) was 91% and 99%, respectively. At the per participant level, the range of survivin expression was 50-100% of the cellular content. The heterogeneity of survivin expression intensity among participants is shown in Figure 1. All participants had some proportion of biopsied cells expressing strong (3+) intensity survivin (range: 5-100% of cells, mean: 30% while only 52% of tumors contained non-survivin expressing (0) cells, ranging from 0% to 50% (mean: 9%) Greater proportions of cells that expressed moderate (2+) and/or strong (3+) survivin significantly correlated with clinical and biological markers of aggressive DLBCL. Non-GCB tumours (11/25) showed greater H-scores compared to GCB tumours (212 vs 167, p = 0.0287). Non-GCB tumours contained greater proportions of strong intensity (3+) survivin cells compared to GCB tumours (44% vs 25%, p= 0.045). In addition, participants with LDH above the upper limit of normal at screening (52%, 13/25) had a greater mean proportion of cells expressing moderate and strong intensity survivin (proportion of 2+ and 3+ combined) (72% vs 54%, p = 0.0447) and a lower mean proportion of weak survivin intensity (1+) cells (p = 0.0374) compared to those with normal LDH. A relationship between total tumor area at baseline and survivin intensity levels was explored. Higher proportions of cells expressing weak intensity (1+) survivin were associated with smaller total tumour area at baseline (p=0.0201). In contrast, higher combined proportions of moderate (2+) and high (3+) intensity survivin was associated with larger total tumour area at baseline (p=0.0285). The significant association with the 2+/3+ intensity of survivin with LDH, cell of origin and tumour burden may suggest a mechanistic threshold in DLBCL pathobiology that drives aggressive clinical behavior. Discussion: Here we demonstrate substantial heterogeneity of survivin protein expression in baseline tumour biopsies of R/R DLBCL patients. Given our findings, it may be of clinical and pathobiological significance to assess both the proportion of survivin-expressing cells as well as the intensity of survivin expression. As the known functions of survivin include protection from apoptosis and cell-cycle progression, the associations demonstrated here support the relevance of survivin and in particular high intensity (2+, 3+) survivin as a biomarker linked with aggressive R/R DLBCL features. These results further support the targeting of survivin pathways in interventional trials and development of validated clinical laboratory survivin assays. Further analysis by multiplex immunofluorescence is in progress to further explore how 2+/3+ vs. 0 host immune cells may also influence survivin immunogenicity and clinical response post-MVP-S immunotherapy.
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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) | 0,000 | 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 ».