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An oncolytic adenovirus targeting SLAMF7 demonstrates anti-myeloma efficacy
Georgia Stewart1,2,3, Simon Tazzyman1,2,3, Yidan Sun1,2,3
1Sheffield Myeloma Research Team, University of Sheffield, Sheffield, UK.
Abstract:
We investigated a novel SLAMF7-promoter driven oncolytic adenovirus (Ad[CE1A]) as a potential therapeutic for multiple myeloma, an incurable hematological malignancy. Ad[CE1A] infection, replication, and oncolysis were assessed in a panel of myeloma cell lines (n = 8) and ex vivo samples from myeloma patients (n = 17) and healthy donors (HDs) (n = 14). Ad[CE1A] efficiently infected, replicated, and induced oncolysis in myeloma cells, but not in control cell lines or HDs, demonstrating selective cytotoxicity. Mechanistic studies revealed Ad[CE1A]-induced cell death is caspase-independent, with a potential involvement of necroptosis. Ad[CE1A] also altered immunogenic cell death markers (calreticulin, CD47, extracellular ATP), enhanced antigen presentation via increased MHC class I and II receptor expression (HLA-ABC and HLA-DR), and stimulated bystander cytokine killing, indicating potential for direct and immune-mediated anti-myeloma responses. In vivo experiments with 5TGM1 syngeneic and U266 xenograft models showed Ad[CE1A] significantly reduced myeloma tumor burden compared to vehicle control. Combination therapy with anti-myeloma drugs, bortezomib, melphalan, panobinostat and pomalidomide, enhanced Ad[CE1A] efficacy, with melphalan upregulating SLAMF7, resulting in increased viral replication. In summary, these findings support Ad[CE1A] as a promising myeloma therapy.
Insights
A novel oncolytic adenovirus, Ad[CE1A], shows promise for treating multiple myeloma. It selectively targets cancer cells, enhances immune responses, and reduces tumor burden, offering a potential new therapy for this incurable disease.
Area of Science:
- Oncolytic virotherapy
- Hematological malignancies
- Cancer immunotherapy
Background:
- Multiple myeloma is an incurable hematological malignancy.
- Novel therapeutic strategies are needed to improve patient outcomes.
Purpose of the Study:
- To investigate a novel SLAMF7-promoter driven oncolytic adenovirus (Ad[CE1A]) as a potential therapeutic for multiple myeloma.
- To assess the efficacy and mechanisms of Ad[CE1A] in preclinical models.
Main Methods:
- Ad[CE1A] infection, replication, and oncolysis were assessed in myeloma cell lines and patient samples.
- Mechanistic studies investigated cell death pathways and immunogenic cell death markers.
- In vivo experiments utilized syngeneic and xenograft models of multiple myeloma.
- Combination therapy with existing anti-myeloma drugs was evaluated.
Main Results:
- Ad[CE1A] demonstrated selective cytotoxicity against myeloma cells, with efficient infection, replication, and oncolysis.
- Cell death was caspase-independent, potentially involving necroptosis.
- Ad[CE1A] modulated immunogenic cell death markers and enhanced antigen presentation.
- In vivo studies showed significant reduction in myeloma tumor burden.
- Combination therapy, particularly with melphalan, enhanced Ad[CE1A] efficacy.
Conclusions:
- Ad[CE1A] is a promising oncolytic adenovirus for multiple myeloma therapy.
- Its selective cytotoxicity and ability to elicit immune responses support its therapeutic potential.
- Combination strategies may further enhance its clinical efficacy.
