Fully Retargeted, Myeloma-Specific Oncolytic Measles Viruses.

We previously reported that attenuated measles viruses have potent anti-tumor activity in primary myeloma cells and myeloma xenograft models. The viruses are selectively oncolytic because they cause extensive cell to cell fusion via CD46, a membrane complement regulatory protein that is more highly expressed on myeloma cells than on normal cells. A phase I clinical trial is planned at Mayo Clinic using an oncolytic measles virus engineered to express the thyroidal sodium iodide symporter gene (MV-NIS). Expected toxicities of MV-NIS include a mild measles-like illness due to residual infection of normal host cells via either of the two natural virus receptors, CD46 and SLAM. To facilitate the development of fully retargeted oncolytic measles viruses we recently developed the pseudoreceptor system “STAR”, which allows rescue and propagation of targeted viruses with modified H proteins that no longer bind to the native measles receptors (Nakamura T. et. al., Nature Biotechnology, 2005). Using the STAR system, we have now generated fully retargeted oncolytic measles viruses against two targets, CD38 or HM1.24 that are highly expressed on the surface of multiple myeloma cells. CD38 is expressed abundantly on myeloma plasma cells but is also expressed in a variety of normal human cells, such as myeloid progenitors and activated T cells. The HM1.24 antigen is highly expressed on terminally differentiated B-cells (including myeloma cells) and is not found on liver, spleen, kidney, or heart. To facilitate evaluation of the receptor specificity of the recombinant viruses, they were each constructed with an additional transgene insert coding for green fluorescent protein (GFP). Efficient viral incorporation of each of the recombinant H proteins was demonstrated by immunoblotting of pelleted virions. CHO cells were transfected with each of the targeted receptors and then infected with each of the targeted viruses. As expected, each virus demonstrated the predicted host range properties and was blind to CD46 and SLAM receptors, but efficiently entered cells through the respective targeted receptor. In addition, these retargeted viruses demonstrated myeloma-specific infection, syncytium formation and cytotoxicity for multiple myeloma cell lines RPIM8226 and KAS-6/1, but not on receptor-negative control cells such as K562 human erythroleukemic cells. These fully retargeted oncolytic measles viruses are promising candidates that may provide the basis for safer and more effective virotherapy in multiple myeloma.