Sindbis virus, a member of the alphavirus genus in the Togaviridae family, is a single-stranded, enveloped, positive-sense RNA virus (Strauss & Strauss, 1994). In nature, it is transmitted via mosquito bites to mammals. Thus, as Sindbis virus has evolved as a blood-borne vector, this hematogenous delivery property enables Sindbis vectors to reach tumor cells throughout the circulation (Tseng et al 2004a,b).
U.S. Pat. No. 7,306,792, which is the National Stage of PCT/US02/09432 published as WO 02/076468 entitled TUMOR THERAPY WITH ALPHAVIRUS-BASED AND HIGH AFFINITY LAMININ RECEPTOR-TARGETED VECTORS discloses methods for treating solid tumors in mammals using Sindbis vectors. The method comprises systemically administering to a mammal harboring a tumor an amount of an Alphavirus vector effective to treat the tumor. The vector was said to have a preferential affinity for high affinity laminin receptors (HALR). Tumor cells which express greater levels of HALR compared to normal cells of the same lineage were preferentially killed by the vector. The anti-tumor effect was said to be due to the fact that Sindbis virus infection induced apoptosis in infected cells.
PCT/US 2004/026671 for A METHOD FOR DETECTING CANCER CELLS AND MONITORING CANCER THERAPY discloses the use of Sindbis viral vectors to identify cancer cells in the body of a mammal and monitor anti-cancer therapy.
U.S. Pat. No. 7,303,898 discloses defective Sindbis virus vectors, novel Helper and Replicon plasmids used to produce the vectors and methods for treating mammals harboring solid tumors which express higher levels of HALR than normal cells of the same lineage.
U.S. Pat. No. 7,378,272 discloses packaging cell lines for the continuous production of defective Sindbis virus vectors.
With the aim of broadening the knowledge of the way Sindbis vectors work for cancer gene therapy, two different kinds of Sindbis vectors, SP6-H/SP6-R, derived from wild type Ar-339, and JT-BB/JT-Rep derived from an Ar-339 laboratory adapted strain, Toto 1101 have been studied. Sindbis virus Ar-339 was first isolated in August 1952, from a pool of mosquitoes (Culex pipiens and C. univittatus) trapped in the Sindbis health district in Egypt (Hurlbut 1953; Taylor and Hurlbut 1953; Frothingham 1955; Taylor et al. 1955). Toto 1101 was made out of the heat resistant (HR) strain initially derived from AR-339 (Burge and Pfefferkorn, 1966). The first studies done with JT vectors in animal models showed good targeting of tumor cells and significant reduction of metastatic implant size (Tseng et al. 2002). Further studies of these vectors in tumor-induced SCID mice were done using the new imaging technique of IVIS®, that allows in vivo detection of viral vector and tumor cells in the same animal. In tumor-induced SCID mice there was a good correlation between vectors and tumor cells (Tseng et al. 2004b). Although these positive results in vector targeting and in vivo growth reduction of tumors and mouse survival, which are very promising for gene therapy, survival of all mice in these tumor models has not yet been achieved.
Therefore, what is need in the art are improved Sindbis viral vectors for use as anti-tumor agents.