New cancer therapy using genetically-engineered oncolytic Sendai virus vector.

We have developed a new type of Sendai virus-(SeV) based gene transfer vectors for cancer therapy. The matrix gene-, indispensable for particle formation, deficient and fusion gene-, essential for cell-fusion and deciding viral tropism, redesigned SeV vector loses vector particle formation from transduced cells and gains cell-to-cell spreading in protease-dependent, namely controllable, manner. For the selective delivery to malignant tumor cells expressing matrix metalloproteinases (MMPs) or urokinase-type plasminogen activator (uPA), we introduced MMP-cleavage (PLGMTS) or uPA-cleavage (SGRS) sequences, respectively, immediately prior to the cleavage site for activation of fusion protein with remaining essential sequences for cell-fusion. The MMP-targeted SeV vector demonstrated syncytia formation in MMP expressing HT1080 cell line in vitro, and growth inhibition of HT1080 subcutaneous xenografts in vivo. The uPA-targeted one showed the same effects in uPA expressing PC-3 cell line. Severe apoptosis occurred in fused-cells. Thus, the vector selectively spreads to tumor cells in tumor-protease dependent manner and demonstrates the antitumor effects in solid tumors, indicating the value of selective targeting and killing of tumors by recombinant SeV technology.