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
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Vile, R.G., Russell, S.J. & Lemoine, N.R. Cancer gene therapy: hard lessons and new courses. Gene Ther. 7, 2–8 (2000).
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).
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).
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).
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).
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).
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).
Dudley, M.E. & Rosenberg, S.A. Adoptive-cell-transfer therapy for the treatment of patients with cancer. Nat. Rev. Cancer 3, 666–676 (2003).
Yee, C., Riddell, S.R. & Greenberg, P.D. In vivo tracking of tumor-specific T cells. Curr. Opin. Immunol. 13, 141–146 (2001).
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).
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).
Dudley, M.E. et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298, 850–854 (2002).
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).
Pizzato, M. et al. Evidence for nonspecific adsorption of targeted retrovirus vector particles to cells. Gene Ther. 8, 1088–1096 (2001).
Weiss, R.A. & Chetankuma, S.T. Retrovirus receptors. Cell 82, 531–533 (1995).
Sasisekharan, R., Shriver, Z., Venkataraman, G. & Narayanasami, U. Roles of heparan-sulphate glycosaminoglycans in cancer. Nat. Rev. Cancer 2, 521–528 (2002).
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).
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).
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).
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).
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).
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).
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).
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).
Bobardt, M.D. et al. Syndecan captures, protects, and transmits HIV to T lymphocytes. Immunity 18, 27–39 (2003).
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).
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).
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).
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).
Hulett, M.D. et al. Cloning of mammalian heparanase, an important enzyme in tumor invasion and metastasis. Nat. Med. 5, 803–809 (1999).
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).
Vlodavsky, I. et al. Mammalian heparanase: gene cloning, expression and function in tumor progression and metastasis. Nat. Med. 5, 793–802 (1999).
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).
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).
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).
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).
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).
Daniels, G. et al. A simple method to cure established tumors by inflammatory killing of normal cells. Nat. Biotechnol. 22, 1125–1132 (2004).
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).
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).
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).
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).
Chernajovsky, Y., Gould, D.J. & Podhajcer, O.L. Gene therapy for autoimmune diseases: quo vadis? Nat. Rev. Immunol. 4, 800–811 (2004).
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).
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).
Markowitz, D., Goff, S. & Bank, A. Construction and use of a safe and efficient amphotropic packaging cell line. Virology 167, 400–406 (1988).
Miller, A.D. et al. Construction and properties of retroviral packaging cells based on gibbon ape leukemia virus. J. Virol. 65, 2220–2224 (1991).
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).
Hogquist, K.A. et al. T cell receptor antagonistic peptides induce positive selection. Cell 76, 17–27 (1994).
Altman, D.G. Analysis of survival times. in Practical Statistics for Medical Research. 365–395 (Chapman and Hall, London, 1991).
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
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights 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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm1297
This article is cited by
-
Rerouting nanoparticles to bone marrow via neutrophil hitchhiking
Nature Nanotechnology (2023)
-
Biological causes of immunogenic cancer cell death (ICD) and anti-tumor therapy; Combination of Oncolytic virus-based immunotherapy and CAR T-cell therapy for ICD induction
Cancer Cell International (2022)
-
Programming CAR T cells to enhance anti-tumor efficacy through remodeling of the immune system
Frontiers of Medicine (2020)
-
Biomaterials for Engineering Immune Responses
Journal of the Indian Institute of Science (2018)
-
Prospects for combined use of oncolytic viruses and CAR T-cells
Journal for ImmunoTherapy of Cancer (2017)