Combination Therapy with Reovirus and Immunomodulatory Drugs Induces Direct Oncolytic and Immune-Mediated Killing of Multiple Myeloma Cells and Overcomes Stromal-Mediated Microenvironmental Protection
Notice bibliographique
Résumé
Abstract Introduction Despite considerable advances in therapy over recent years, multiple myeloma (MM) remains largely incurable with a clinical course characterised by ever-shortening periods of treatment and relapse; new therapies with novel mechanisms of action are needed. The immunomodulatory agents (IMiDs) in current clinical practice can augment immune effector function and combination with other immunologically active agents is a rational avenue of investigation – indeed trials of IMiDs with agents such as monoclonal antibody therapies are already underway. The naturally occurring oncolytic virus reovirus serotype 3 Dearing (Reolysin, Oncolytics Biotech Inc) has been shown to be safe in the context of advanced epithelial-derived cancers, and more recently in patients with MM. In this study we demonstrate the potential of reovirus in combination with IMiDs and steroids to induce both direct tumour cell killing and an anti-tumour immune response, particularly in the context of the cytoprotective effect of stromal cell interactions. Methods Human myeloma cell lines (HMCLs) were tested for JAM1 expression (the high affinity receptor for reovirus) by flow cytometry (FACS). HMCLs, alone or in co-culture with human stromal cell lines, were treated with reovirus at a range of multiplicities of infection (MOIs), alone or in combination with lenalidomide and/or dexamethasone and examined by flow cytometry to determine time- and concentration- dependent cell death. Peripheral blood mononuclear cells (PBMC) from healthy donors and patients were treated with reovirus/drug combinations and immune effector cell activation determined by surface expression of CD69. Treated PBMC and untreated HMCL were co-cultured and NK cell degranulation and NK cell-mediated HMCL cell death was determined. Bone marrow aspirate samples (BM) were collected from patients with MM, treated with reovirus, lenalidomide and dexamethasone combinations, and examined by FACS for killing of CD138+ cells and immune effector cell activation. Results JAM1 was expressed on the HMCLs H929, JIM3, KMS11, KMS18, JJN3 and U266B, but not on OPM2. All lines except OPM2 (which was resistant) were susceptible to reovirus-induced oncolysis in a time- and MOI-dependent manner. Addition of dexamethasone and lenalidomide to these treatments further increased the killing of tumour cells. Reovirus treatment induced upregulation of CD69 on NK cells, CD4+ T cells, CD8+ T cells and NKT cells isolated from the peripheral blood of both healthy donors and patients with MM. Healthy donor NK cells activated ex vivo with reovirus showed augmented degranulation (by surface CD107a expression) and killing of HMCL tumour targets. Importantly, in the case of OPM2, which was resistant to direct viral-induced cell death, reovirus-activated NK cells killed the HMCL. NK cells from MM patients showed enhanced degranulation against autologous tumour cells. Cell contact-independent killing of HMCL by reovirus-treated PBMC was also noted. Coculture of HMCLs with human bone marrow stromal cell lines (HS-5 and HS-27) protected against lenalidomide- and dexamethasone-induced HMCL cell death. However, treatment with reovirus overcame this cytoprotection. In keeping with this, when BM from MM patients was treated with lenalidomide and/or dexamethasone, the addition of reovirus augmented killing of CD138+MM cells. Conclusions Our data indicate reovirus has dual modes of action against MM – not only can the virus mediate direct oncolytic cytotoxicity against the malignant clone, but in addition it can activate immune effector cells and thus induce immunologically-mediated tumour killing. Importantly, this immune-mediated action was noted even against HMCLs resistant to the direct viral effects. Furthermore, the cytoprotection and immune evasion afforded by stromal cells was mitigated by reovirus therapy and thus addition of reovirus to established immunomodulatory myeloma therapies augments their efficacy. Reovirus-based immunomodulatory combination therapies are a rational therapeutic approach for patients with relapsed MM and warrant further investigation in the pre-clinical and early phase clinical trial setting. Disclosures Coffey: Oncolytics Biotech Inc.: Employment.
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 ».