Oncolytic Measles Virus Selectively Targets CD46 Overexpression on Myeloma Cells.

Multiple myeloma remains incurable and novel therapeutics are urgently needed. We have shown that live attenuated Edmonston strain measles virus (MV-Edm) is potently oncolytic in multiple myeloma xenograft models and can efficiently infect CD138 sorted primary myeloma cells inducing extensive intercellular fusion which leads to cell death (Blood, 2001, v98, p2002). In contrast, the virus causes minimal damage to normal PHA-stimulated peripheral blood lymphocytes, fibroblasts and smooth muscle cells. To facilitate non-invasive imaging of sites of viral gene expression, we introduced the human thyroidal sodium iodide symporter (NIS) gene into the viral genome (MV-NIS). MV-NIS infected myeloma cells efficiently concentrate radioiodine which provides a basis for noninvasive imaging and destruction of infected tumors using beta emitters such as 131I (Blood, 2004, v103, p1641). Clinical translation of MV-NIS in patients with refractory myeloma is planned. However, the mechanism underlying the tumor selectivity of MV-Edm has not previously been defined. MV-Edm uses either of two cellular receptors for cell entry and cell fusion; CD46, a regulator of complement activation, is expressed on all nucleated cells, wheras SLAM (signaling lymphocyte activation molecule) is expressed only on activated B lymphocytes, T lymphocytes, and monocytes, and is not present on myeloma plasma cells. Using a panel of CHO cell transfectants, we demonstrated that MV-Edm -mediated cell killing increases exponentially above a threshold CD46 receptor density (Can Res, 2004, v64, p4919). We subsequently obtained bone marrow aspirates from 18 myeloma patients and performed multi-parameter flow cytometry to determine the relative expression levels of CD46 on the myeloma plasma cells versus the rest of the hematopoietic cells in the bone marrow. The myeloma cells expressed significantly higher levels (5-fold) of CD46 receptors (MFI=294.9 + 204.4, means ± SD) on their cell surfaces compared to hematopoietic cells of the erythroid, myeloid and lymphoid lineages (MFI=58.6 ± 9.0). Analysis of the myeloma array data generated by the Shaughnessy lab indicated that, in comparison to plasma cells from healthy volunteers (2997 ± 1053, n=30, means ± SD), primary myeloma cells express 2-fold elevated levels of CD46 mRNA (6592 ± 4029, n=72, p=0.001, Wilcoxon signed rank test). Taken together, these findings provide strong support for the hypothesis that selective destruction of myeloma cells by oncolytic measles viruses is a direct consequence of their overexpression of the cellular receptor CD46.