Abstract
Multiple myeloma (MM) is a plasma cell malignancy that is characterized by immune dysregulation. MM is commonly treated with immunomodulating agents, but still remains incurable. Herein, we proposed and evaluated immunostimulatory Lokon oncolytic adenoviruses (LOAd) for MM treatment. LOAd viruses are serotype 5/35 chimera, which enables infection of hematopoietic cells. Oncolysis is restricted to cells with a dysregulated retinoblastoma protein pathway, which is frequently observed in MM. Further, LOAd viruses are armed with human immunostimulatory transgenes: trimerized membrane-bound CD40L (LOAd700, LOAd703) and 4-1BBL (LOAd703). LOAd viruses were assessed in a panel of MM cell lines (ANBL-6, L363, LP-1, OPM-2, RPMI-8226, and U266-84). All cells were sensitive to infection, leading to viral replication and cell killing as analyzed by quantitative PCR and viability assay. Transgene expression was verified post infection with flow cytometry. Cell phenotypes were further altered with a downregulation of markers connected to MM progression (ICAM-1, CD70, CXCL10, CCL2, and sIL-2Rα) and an upregulation of the death receptor Fas. In a co-culture of immune and MM cells, LOAd viruses promoted activation of cytotoxic T cells as seen by higher CD69, CD107a, and IFNγ expression. This was most prominent with LOAd703. In conclusion, LOAd viruses are of interest for MM therapy.
Highlights
Multiple myeloma (MM) is a plasma cell malignancy and the second most common hematological cancer type with an incidence rate of 5 cases per 100,000 people in the Western world
To determine the oncolytic capacity of Lokon oncolytic adenoviruses (LOAd) viruses, MM cell lines were infected with LOAd viruses or replication-deficient Ad5/35 Mock virus (E1/E3 deleted) at different virus to cell ratios (10, 20, 50, and 200 MOI)
OPM-2 appeared especially sensitive as Mock virus killed the cells to a similar extent as LOAd viruses
Summary
Multiple myeloma (MM) is a plasma cell malignancy and the second most common hematological cancer type with an incidence rate of 5 cases per 100,000 people in the Western world. Even though current treatment options have improved the overall survival to a median of 6 years, MM still remains incurable [1, 2]. Patients with high-risk MM with presence of extramedullary disease (infiltrates in soft tissue or visceral organs) have an especially bad prognosis with no effective treatment options available [3, 4]. The development of novel therapies is of particular importance for this patient
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