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Tumor-targeted, systemic delivery of therapeutic viral vectors using hitchhiking on antigen-specific T cells

Abstract

Antigen-specific T cells circulate freely and accumulate specifically at sites of antigen expression. To enhance the survival and targeting of systemically delivered viral vectors, we exploited the observation that retroviral particles adhere nonspecifically, or 'hitchhike,' to the surface of T cells. Adoptive transfer of antigen-specific T cells, loaded with viruses encoding interleukin (IL)-12 or Herpes Simplex Virus thymidine kinase (HSVtk), cured established metastatic disease where adoptive T-cell transfer alone was not effective. Productive hand off correlated with local heparanase expression either from malignant tumor cells and/or as a result of T-cell activation by antigen, providing high levels of selectivity for viral transfer to metastatic tumors in vivo. Protection, concentration and targeting of viruses by adsorption to cell carriers represent a new technique for systemic delivery of vectors, in fully immunocompetent hosts, for a variety of diseases in which delivery of genes may be therapeutically beneficial.

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Figure 1: Retroviral particles hitch hike on T cells and can be handed off to infect co-cultured tumor cells.
Figure 2: Viral hitchhiking or hand off is inhibited by HSG.
Figure 3: Hitchhiking enhances adoptive T-cell therapy.
Figure 4: Hitchhiking enhances cytotoxic gene therapy.
Figure 5: HSVtk viral hand off in immunodepleted hosts leads to expansion of adoptively transferred T cells.

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Acknowledgements

The authors thank T.L. Higgins for secretarial assistance. This work was supported by the Mayo Foundation and by US National Institutes of Health grants 1RO1CA94180 and 1RO1CA107082 (to R.V.).

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Correspondence to Richard G Vile.

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Cole, C., Qiao, J., Kottke, T. et al. Tumor-targeted, systemic delivery of therapeutic viral vectors using hitchhiking on antigen-specific T cells. Nat Med 11, 1073–1081 (2005). https://doi.org/10.1038/nm1297

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