913 Translational analysis of advanced metastatic bladder cancer patients treated with IO combination maveropepimut-S, cyclophosphamide, and pembrolizumab
Notice bibliographique
Résumé
<h3>Background</h3> Maveropepimut-S (MVP-S, formerly DPX-Survivac) is comprised of immunogenic T cell peptides from the cancer antigen, survivin, as well as a universal T helper peptide, A16L, and the innate immune activator, poly-dIdC, packed within the proprietary DPX<sup>®</sup> lipid-in-oil delivery platform. When combined with intermittent low-dose cyclophosphamide (CPA), and the immune checkpoint inhibitor, pembrolizumab, the proprietary DPX lipid-in-oil delivery platform elicits a sustained immune response that has been associated with clinical benefit in multiple tumor types. Here, we present translational analyses of immune cell infiltration and peripheral, cell-mediated immunity in advanced metastatic bladder cancer subjects (n=19) from this Phase 2 trial, NCT03836352. <h3>Methods</h3> Survivin specific immune response was measured in PBMCs by IFN-? ELISPOT (n=14) and MHC-Tetramer assay (n=13). Multiplex immunofluorescence (mIF) (n=5) was performed by Precision for Medicine. PD-L1 status (n=13) was analyzed using the 22C3 IHC assay at Covance. Gene expression analysis was performed using the NanoString IO360 panel (n=11). <h3>Results</h3> Analysis of PBMCs by IFN-? ELISPOT or MHC-tetramer assay demonstrates antigen-specific cell response in 71.4% (10/14) of evaluable patients, and in all five patients with measurable tumor responses. Baseline profiling of RNA signatures suggests that levels of B, T, and NK cells are higher in tumors of responding patients similar to previous MVP-S trials (DeCidE<sup>1</sup>; NCT02785250). Preliminary mIF also shows that one complete responder (RECISTv1.1) has a higher density of infiltrate, including CD8+ cells, at baseline. Grouped analysis of five on-treatment samples suggests higher immune resistance pathways such as TGF and CD71<sup>+</sup> early erythroid cells, in non-responding patients, which has been linked to immune tolerance and suppression of T cells.<sup>1</sup> mIF of five paired pre- and on-treatment biopsies reveals higher levels of FoxP3<sup>+</sup> (T<sub>regs</sub>) in post-treatment tumour of non-responders whereas the reverse is observed in tissue of responders. PD-L1 staining of pre-treatment tumor tissue by IHC, shows (4/4) of evaluable responding patients had a CPS score of ≥1%. <h3>Conclusions</h3> The combination of MVP-S, CPA, and anti-PD-1 therapy provides a renewed approach directly targeting the TAA survivin and imposing a limit on immune suppression with CPA along with checkpoint inhibition. The data herein show that the treatment of advanced metastatic bladder cancer with MVP-S plus CPA in combination with pembrolizumab elicits a strong survivin-specific immune cell response in addition to the clinical response as reported previously (AACR 2022). Taken together, the translational data demonstrate that this novel immune oncology approach leads to immune education that is correlated with improved disease control. <h3>Reference</h3> Grzywa TM, Sosnowska A, Rydzynska Z, <i>et al</i>. Potent but transient immunosuppression of T-cells is a general feature of CD71+ erythroid cells. <i>Commun Biol</i> 2021;<b>4</b>:1384. doi: 10.1038/s42003-021-02914-4. <h3>Ethics Approval</h3> WIRB (20183396); Cedars-Sinai Medical Center Institutional Review Boards (Pro00057155); The University of Texas MD Anderson Cancer Center Institutional Review Board (IRB 2) (2019-0135); Ochsner Clinic Foundation Institutional Review Board (2019 084); University of Louisville IRB # 1 – Biomedical (19.045); WCG IRB (20183396); Willima Osler Health System Research Ethics Board (18-0064); Ontario Cance Research Ethics Board (OCREB) (1732); Comite d9ethique de la recherche du CHU de Quebec – Universite Laval (MP-20-2019-4582*;
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 | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 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 ».