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Systemic tumor targeting and killing by Sindbis viral vectors

Abstract

Successful cancer gene therapy requires a vector that systemically and specifically targets tumor cells throughout the body. Although several vectors have been developed to express cytotoxic genes via tumor-specific promoters or to seclectively replicate in tumor cells, most are taken up and expressed by just a few targeted tumor cells. By contrast, we show here that blood-borne Sindbis viral vectors systemically and specifically infect tumor cells. A single intraperitoneal treatment allows the vectors to target most tumor cells, as demonstrated by immunohistochemistry, without infecting normal cells. Further, Sindbis infection is sufficient to induce complete tumor regression. We demonstrate systemic vector targeting of tumors growing subcutaneously, intrapancreatically, intraperitoneally and in the lungs. The vectors can also target syngeneic and spontaneous tumors in immune-competent mice. We document the anti-tumor specificity of a vector that systemically targets and eradicates tumor cells throughout the body without adverse effects.

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Figure 1: Intraperitoneal delivery of a Sindbis vector, Sindbis/luc, to SICD mice bearing s.c. BHK tumors results in tumor-specific infection and tumor growth suppression.
Figure 2: Single i.p. delivery of Sindbis/lacZ vectors specifically infected intrapancreatic BHKSINLuc2 tumors, which require Sindbis infection for luciferase gene expression.
Figure 3: Intravenous delivery of Sindbis/luc vectors targeted BHK tumors in the lung, which were induced by i.v. injection of BHK cells.
Figure 4: Intraperitoneal treatment with Sindbis vectors specifically infected microscopic metastasized ES-2 ovarian tumors in the peritoneal cavity and significantly suppressed disease progress.
Figure 5: Sindbis vector can target syngenic Pan02 s.c. tumor in immune-competent mouse.
Figure 6: Sindbis vector can target spontaneous tumors in RGR/p15+/− transgenic mice that develop tumors on the tail or paws.

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Acknowledgements

We thank Elizabeth W. Newcomb, Christine Pampeno and Colby Collier for critical reading of this manuscript and helpful discussions. This study was supported by US Public Health Service grants CA22247 and CA68498 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, by U.S. Army grant 0C000111 and by a generous gift from the Karan-Weiss Foundation.

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Correspondence to Daniel Meruelo.

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Tseng, JC., Levin, B., Hurtado, A. et al. Systemic tumor targeting and killing by Sindbis viral vectors. Nat Biotechnol 22, 70–77 (2004). https://doi.org/10.1038/nbt917

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