Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

References

  1. Vile, R.G., Russell, S.J. & Lemoine, N.R. Cancer gene therapy: hard lessons and new courses. Gene Ther. 7, 2–8 (2000).

    Article  CAS  Google Scholar 

  2. Harrington, K. et al. Cells as vehicles for cancer gene therapy: The missing link between targeted vectors and systemic delivery. Hum. Gene Ther. 13, 1263–1280 (2002).

    Article  CAS  Google Scholar 

  3. Pizzato, M., Marlow, S.A., Blair, E.D. & Takeuchi, Y. Initial binding of murine leukemia virus particles to cells does not require specific Env-receptor interaction. J. Virol. 73, 8599–8611 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Chester, J. et al. Tumor antigen-specific induction of transcriptionally targeted retroviral vectors from chimeric immune receptor-modified T cells. Nat. Biotechnol. 20, 256–263 (2002).

    Article  CAS  Google Scholar 

  5. Crittenden, M. et al. Pharmacologically regulated production of targeted retrovirus from T cells for systemic anti-tumor gene therapy. Cancer Res. 63, 3173–3180 (2003).

    CAS  PubMed  Google Scholar 

  6. Harrington, K.J., Linardakis, E. & Vile, R.G. Transcriptional control: an essential component of cancer gene therapy strategies? Adv. Drug Deliv. Rev. 44, 167–184 (2000).

    Article  CAS  Google Scholar 

  7. Rosenberg, S.A. & Dudley, M.E. Cancer regression in patients with metastatic melanoma after the transfer of autologous antitumor lymphocytes. Proc. Natl. Acad. Sci. USA 101, Suppl. 2, 14639–14645 (2004).

    Article  CAS  Google Scholar 

  8. Dudley, M.E. & Rosenberg, S.A. Adoptive-cell-transfer therapy for the treatment of patients with cancer. Nat. Rev. Cancer 3, 666–676 (2003).

    Article  CAS  Google Scholar 

  9. Yee, C., Riddell, S.R. & Greenberg, P.D. In vivo tracking of tumor-specific T cells. Curr. Opin. Immunol. 13, 141–146 (2001).

    Article  CAS  Google Scholar 

  10. Yee, C. et al. Melanocyte destruction after antigen-specific immunotherapy of melanoma: direct evidence of T cell-mediated vitiligo. J. Exp. Med. 192, 1637–1644 (2000).

    Article  CAS  Google Scholar 

  11. Dudley, M.E. et al. Adoptive transfer of cloned melanoma-reactive T lymphocytes for the treatment of patients with metastatic melanoma. J. Immunother. 24, 363–373 (2001).

    Article  CAS  Google Scholar 

  12. Dudley, M.E. et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298, 850–854 (2002).

    Article  CAS  Google Scholar 

  13. Palmer, D. et al. Vaccine-stimulated, adoptively transferred CD8+ T cells traffic indiscriminately and ubiquitously while mediating specific tumor destruction. J. Immunol. 173, 7209–7216 (2004).

    Article  CAS  Google Scholar 

  14. Pizzato, M. et al. Evidence for nonspecific adsorption of targeted retrovirus vector particles to cells. Gene Ther. 8, 1088–1096 (2001).

    Article  CAS  Google Scholar 

  15. Weiss, R.A. & Chetankuma, S.T. Retrovirus receptors. Cell 82, 531–533 (1995).

    Article  CAS  Google Scholar 

  16. Sasisekharan, R., Shriver, Z., Venkataraman, G. & Narayanasami, U. Roles of heparan-sulphate glycosaminoglycans in cancer. Nat. Rev. Cancer 2, 521–528 (2002).

    Article  CAS  Google Scholar 

  17. Linardakis, E. et al. Enhancing the efficacy of a weak allogeneic melanoma vaccine by viral fusogenic membrane glycoprotein-mediated tumor cell-tumor cell fusion. Cancer Res. 62, 5495–5504 (2002).

    CAS  PubMed  Google Scholar 

  18. de Mestre, A.M., Khachigian, L.M., Santiago, F.S., Staykova, M.A. & Hulett, M.D. Regulation of inducible heparanase gene transcription in activated T cells by early growth response 1. J. Biol. Chem. 278, 50377–50385 (2003).

    Article  CAS  Google Scholar 

  19. Takeuchi, Y., Cosset, F.L., Lachmann, P.J., Okada, H., Weiss, R.A. & Collins, M.K.L. Type C retrovirus inactivation by human complement is determined by both the viral genome and the producer cell. J. Virol. 68, 8001–8007 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Chong, H., Todryk, S., Hutchinson, G., Hart, I.R. & Vile, R.G. Tumour cell expression of B7 costimulatory molecules and interleukin-12 or granulocyte-macrophage colony stimulating factor induces a local antitumour response and may generate systemic protective immunity. Gene Ther. 5, 223–232 (1998).

    Article  CAS  Google Scholar 

  21. Vile, R.G. & Hart, I.R. Use of tissue-specific expression of the herpes simplex virus thymidine kinase gene to inhibit growth of established murine melanomas following direct intratumoral injection of DNA. Cancer Res. 53, 3860–3864 (1993).

    CAS  PubMed  Google Scholar 

  22. Vile, R., Miller, N., Chernajovsky, Y. & Hart, I.R. A comparison of the properties of different retroviral vectors containing the murine tyrosinase promoter to achieve transcriptionally targeted expression of the HSVtk or IL-2 genes. Gene Ther. 1, 307–316 (1994).

    CAS  PubMed  Google Scholar 

  23. Diaz, R.M., Eisen, T., Hart, I.R. & Vile, R.G. Exchange of viral promoter/enhancer elements with heterologous regulatory sequences generates targeted hybrid long terminal repeat vectors for gene therapy of melanoma. J. Virol. 72, 789–795 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Geijtenbeek, T.B. et al. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 100, 587–597 (2000).

    Article  CAS  Google Scholar 

  25. Bobardt, M.D. et al. Syndecan captures, protects, and transmits HIV to T lymphocytes. Immunity 18, 27–39 (2003).

    Article  CAS  Google Scholar 

  26. Yotnda, P., Savoldo, B., Charlet-Berguerand, N., Rooney, C. & Brenner, M. Targeted delivery of adenoviral vectors by cytotoxic T cells. Blood 104, 2272–2280 (2004).

    Article  CAS  Google Scholar 

  27. Walker, S.J., Pizzato, M., Takeuchi, Y. & Devereux, S. Heparin binds to murine leukemia virus and inhibits Env-independent attachment and infection. J. Virol. 76, 6909–6918 (2002).

    Article  CAS  Google Scholar 

  28. Saksela, O., Moscatelli, D., Sommer, A. & Rifkin, D.B. Endothelial cell-derived heparan sulfate binds basic fibroblast growth factor and protects it from proteolytic degradation. J. Cell Biol. 107, 743–751 (1988).

    Article  CAS  Google Scholar 

  29. Reiland, J. et al. Heparanase degrades syndecan-1 and perlecan heparan sulfate: functional implications for tumor cell invasion. J. Biol. Chem. 279, 8047–8055 (2004).

    Article  CAS  Google Scholar 

  30. Hulett, M.D. et al. Cloning of mammalian heparanase, an important enzyme in tumor invasion and metastasis. Nat. Med. 5, 803–809 (1999).

    Article  CAS  Google Scholar 

  31. Miao, H.Q. et al. Inhibition of heparanase activity and tumor metastasis by laminarin sulfate and synthetic phosphorothioate oligodeoxynucleotides. Int. J. Cancer 83, 424–431 (1999).

    Article  CAS  Google Scholar 

  32. Vlodavsky, I. et al. Mammalian heparanase: gene cloning, expression and function in tumor progression and metastasis. Nat. Med. 5, 793–802 (1999).

    Article  CAS  Google Scholar 

  33. Tatsumi, T., Gambotto, A., Robbins, P.D. & Storkus, W.J. Interleukin 18 gene transfer expands the repertoire of anti tumor Th-1 type immunity elicited by dendritic cell based vaccines in association with enhanced therapeutic efficacy. Cancer Res. 62, 5853–5858 (2002).

    CAS  PubMed  Google Scholar 

  34. Vile, R.G. et al. Generation of an anti-tumour immune response in a non-immunogenic tumour: HSVtk-killing in vivo stimulates a mononuclear cell infiltrate and a Th1-like profile of intratumoural cytokine expression. Int. J. Cancer 71, 267–274 (1997).

    Article  CAS  Google Scholar 

  35. Melcher, A. et al. Tumor immunogenicity is determined by the mechanism of cell death via induction of heat shock protein expression. Nat. Med. 4, 581–587 (1998).

    Article  CAS  Google Scholar 

  36. Todryk, S. et al. Heat shock protein 70 induced during tumor cell killing induces Th1 cytokines and targets immature dendritic cell precursors to enhance antigen uptake. J. Immunol. 163, 1398–1408 (1999).

    CAS  PubMed  Google Scholar 

  37. Robbins, P.F. et al. Persistence of transferred lymphocyte clonotypes correlates with cancer regression in patients receiving cell transfer therapy. J. Immunol. 173, 7125–7130 (2004).

    Article  CAS  Google Scholar 

  38. Daniels, G. et al. A simple method to cure established tumors by inflammatory killing of normal cells. Nat. Biotechnol. 22, 1125–1132 (2004).

    Article  CAS  Google Scholar 

  39. Hacein-Bey-Abina, S. et al. LMO2-associated clonal T cell proliferations in two patients after gene therapy for SCID-X1. Science 302, 415–419 (2003).

    Article  CAS  Google Scholar 

  40. Qiao, J., Diaz, R.M. & Vile, R. Success for gene therapy: render unto Caesar that which is Caesar's. Genome Biol. 5, 237–240 (2004).

    Article  Google Scholar 

  41. Miller, D.G., Adam, M.A. & Miller, A.D. Gene transfer by retrovirus vectors occurs only in cells that are actively replicating at the time of infection. Mol. Cell. Biol. 10, 4239–4242 (1990).

    Article  CAS  Google Scholar 

  42. Blomer, U., Gruh, I., Witschel, H., Haverich, A. & Martin, U. Shuttle of lentiviral vectors via transplanted cells in vivo. Gene Ther. 12, 67–74 (2005).

    Article  CAS  Google Scholar 

  43. Chernajovsky, Y., Gould, D.J. & Podhajcer, O.L. Gene therapy for autoimmune diseases: quo vadis? Nat. Rev. Immunol. 4, 800–811 (2004).

    Article  CAS  Google Scholar 

  44. Morgenstern, J.P. & Land, H. Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line. Nucleic Acids Res. 18, 3587–3596 (1990).

    Article  CAS  Google Scholar 

  45. Wagner, M.J., Sharp, J.A. & Summers, W.C. Nucleotide sequence of the thymidine kinase gene of herpes simplex virus type 1. Proc. Natl. Acad. Sci. USA 78, 1441–1445 (1981).

    Article  CAS  Google Scholar 

  46. Markowitz, D., Goff, S. & Bank, A. Construction and use of a safe and efficient amphotropic packaging cell line. Virology 167, 400–406 (1988).

    Article  CAS  Google Scholar 

  47. Miller, A.D. et al. Construction and properties of retroviral packaging cells based on gibbon ape leukemia virus. J. Virol. 65, 2220–2224 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Burns, J.C., Friedmann, T., Driever, W., Burrascano, M. & Yee, J.K. Vesicular stomatitis virus G glycoprotein pseudotyped retroviral vectors: concentration to very high titer and efficient gene transfer into mammalian and nonmammalian cells. Proc. Natl. Acad. Sci. USA 90, 8033–8037 (1993).

    Article  CAS  Google Scholar 

  49. Hogquist, K.A. et al. T cell receptor antagonistic peptides induce positive selection. Cell 76, 17–27 (1994).

    Article  CAS  Google Scholar 

  50. Altman, D.G. Analysis of survival times. in Practical Statistics for Medical Research. 365–395 (Chapman and Hall, London, 1991).

    Google Scholar 

Download references

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.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Richard G Vile.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1297

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing