Immunostimulatory oncolytic virotherapy for multiple myeloma targeting 4-1BB and/or CD40

Area of Science:

• Oncology
• Virology
• Immunology

Background:

• Multiple myeloma (MM) is an incurable plasma cell malignancy with significant immune dysregulation.
• Current treatments, primarily immunomodulating agents, have limitations in eradicating MM.
• There is a need for novel therapeutic strategies to overcome MM's resistance to treatment.

Purpose of the Study:

• To evaluate the efficacy of immunostimulatory Lokon oncolytic adenoviruses (LOAd) as a potential treatment for multiple myeloma.
• To assess the oncolytic activity and immune-stimulating properties of LOAd viruses in MM models.

Main Methods:

• LOAd viruses, a serotype 5/35 chimera, were engineered with immunostimulatory transgenes (CD40L and 4-1BBL).
• MM cell lines were infected with LOAd viruses to assess viral replication, cell killing, and transgene expression.
• Phenotypic changes in MM cells and immune cell activation were analyzed using flow cytometry and quantitative PCR.

Main Results:

• All tested MM cell lines were sensitive to LOAd infection, showing viral replication and subsequent cell death.
• LOAd viruses modulated MM cell surface markers, downregulating progression-associated molecules and upregulating Fas.
• Co-culture experiments demonstrated LOAd-induced activation of cytotoxic T cells, evidenced by increased CD69, CD107a, and IFNγ expression, particularly with LOAd703.

Conclusions:

• LOAd viruses exhibit potent oncolytic activity against multiple myeloma cells.
• These engineered adenoviruses possess immunostimulatory capabilities, enhancing anti-tumor immune responses.
• LOAd viruses, especially LOAd703, represent a promising therapeutic candidate for multiple myeloma treatment.