Combination Therapy with Reovirus and Immunomodulatory Drugs Induces Direct Oncolytic and Immune-Mediated Killing of Multiple Myeloma Cells and Overcomes Stromal-Mediated Microenvironmental Protection
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".