Abstract 2539
Background
Despite current treatment options in multiple myeloma (MM), most patients acquire resistance to therapy and relapse. As MM remains incurable, novel therapies are needed. A potentially promising approach is immunostimulatory therapy via an armed oncolytic adenovirus. The herein investigated LOAd viruses are serotype Ad5/35 chimera and therefore infect cells via CD46, which is often upregulated in MM. Viral replication is restricted to tumor cells due to a deletion in E1A. LOAd viruses express transgenes under the control of a CMV promoter. LOAd703 encodes for trimerized membrane-bound (TMZ) CD40L and 4-1BBL, whereas LOAd713 carries a gene encoding a single chain fragment against the IL-6 receptor in combination with TMZ-CD40L. IL-6 is identified as an essential growth and survival factor in MM. Hence, LOAd713 therapy may be of special interest as it not only induces immune cell activation via TMZ-CD40L but also blocks IL-6R signaling.
Methods
A panel of MM cell lines (ANBL-6, L363, LP-1, OPM-2, RPMI-8226, U266-84) were infected with LOAd viruses. Viral replication was evaluated with qPCR detecting viral DNA and viability was analyzed by MTS assay. Surface expression of TMZ-CD40L, 4-1BBL and markers for an immunogenic phenotype were analyzed by flow cytometry. Cell culture supernatants were investigated by multiplex analysis.
Results
All MM cell lines were sensitive to LOAd infection, leading to viral replication and decreased cell viability. TMZ-CD40L and 4-1BBL were expressed in all cells infected with the respective viruses carrying the transgenes. LOAd infection induced an immunogenic phenotype with the upregulation of molecules that facilitate recognition and killing by the immune system. These included CD40, 4-1BB, Fas, HLA-DR, CD80 and CD86. In the supernatants of infected cells, the pro-inflammatory cytokine MIP-1α was increased in 4/6 cell lines. The suggested MM growth factor MCP-1 as well as sIL2R were decreased in 3/6 cell lines.
Conclusions
LOAd viruses infected and replicated in MM cells. The encoding transgenes induced transgene expression and subsequently an immunogenic phenotype in infected cells. Immunostimulatory oncolytic LOAd viruses may be an attractive approach for MM therapy.
Clinical trial identification
Legal entity responsible for the study
Uppsala University, Department of Immunology, Genetics and Pathology, Loskog group.
Funding
The Swedish Cancer Society, The Swedish Research Council, Lokon Pharma AB.
Editorial Acknowledgement
Disclosure
A. Loskog: CEO, board member, royalty agreement, research grant: Lokon Pharma AB; Advisor: Nexttobe AB; Board member: Hansa Medical, Bioimics; Chairman: Repos Pharma, Vivolux; Royalty agreement: Alligator Bioscience. All other authors have declared no conflicts of interest.
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