Gene Therapy That Safely Targets and Kills Tumor Cells Throughout the Body

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Abstract
The authors studied the therapeutic value of Sindbis vectors for advanced metastatic cancer by using a variety of clinically accurate mouse models and demonstrated through imaging, histological, and molecular data that Sindbis vectors systemically and specifically infect/detect and kill metastasized tumors in vivo, leading to significant suppression of tumor growth and enhanced survival. Use of two different bioluminescent genetic markers for the IVIS Imaging System (Xenogen Corp., Alameda, CA) permitted demonstration of an excellent correlation between vector delivery and metastatic locations in vivo. Sindbis tumor specificity is not attributable to a species difference between human tumor and mouse normal cells. Sindbis virus is known to infect mammalian cells using the Mr 67,000 laminin receptor, which is elevated in tumor versus normal cells, and downregulated expression of laminin receptor with small interfering RNA significantly reduces the infectivity of Sindbis vectors. Tumor overexpression of the laminin receptor may explain the specificity and efficacy that Sindbis vectors demonstrate for tumor cells in vivo. Laser capture microdissection of mouse tumor implants showed equivalent laminin receptor expression levels in the different tumor metastases in the peritoneal cavity. Incorporation of antitumor cytokine genes such as interleukin-12 and interleukin-15 genes enhances the efficacy of the vector. These results suggest that Sindbis viral vectors may be promising agents for both specific detection and growth suppression of metastatic ovarian cancer.

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