Sindbis viral vectors as efficient agents for systemic detection and treatment of cancer in animal models
Successful cancer gene therapy requires a vector that systemically and specifically targets tumor cells throughout the body. Vectors based on Sindbis virus, an alphavirus transmitted by mosquitoes, have several unique features that make them promising agents for successful cancer gene therapy. First, Sindbis vectors infect mammalian cells via the high affinity laminin receptors (LAMR), which are expressed at higher levels in several human cancers than in most normal cells. Immunohistochemical staining of tumor cells indicates that LAMR is elevated in tumor vs. normal cells and a single treatment allows the vectors to target most tumor cells without infecting normal cells. Down-regulated expression of LAMR with siRNA significantly reduces the infectivity of Sindbis vectors. Second, Sindbis vectors are natural blood-borne vectors capable of systemic tumor targeting in vivo. Immunohistochemistry studies indicated that vector infection is associated with tumor vascular structures and suggested a vector delivery pathway via the bloodstream. In addition, systemic vector targeting of tumors growing subcutaneously (s.c.), intrapancreatically, intraperitoneally (i.p.), and in the lungs was observed using the IVIS ® Imaging System that detects bioluminescent signals resulting from vector infection. The vectors are also capable of systemically targeting syngeneic and spontaneous tumors in immune competent animals. Third, Sindbis vectors induce apoptosis in tumors after infection. Tumors from Sindbis treated mice contained more apoptotic cells than control tumors as indicated by TUNEL staining. In some cases, repetitive Sindbis treatments induced complete tumor regression. Fourth, Sindbis vectors can efficiently express transgene payload after infection. By carrying proper transgenes, such as anti-tumor cytokine (IL-12 or IL-15), Sindbis vectors demonstrated enhanced anti-tumor efficacy. In addition, the ability to efficiently express HSVtk suicide gene renders Sindbis vector an ideal vector for gene-directed enzyme/prodrug therapy (GDEPT) for cancer. High levels of HSVtk expression ensures not only sufficient prodrug ganciclovir activation for tumor eradication, but also provides a means for non-invasive imaging of HSVtk activity using positron emission tomography (PET) which might significantly improve the dosing for prodrug treatments.
0307: Molecular biology