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.

  • Review
  • Published:

Review Article

Adenoviral vectors: Systemic delivery and tumor targeting

Abstract

The development of a targeted adenoviral vector, which can be delivered systemically, is one of the major challenges facing cancer gene therapy. The virus is readily cleared from the bloodstream, can be neutralised by pre-existing antibodies, and has a permissive cellular tropism. Clinical studies using the ONYX virus have shown limited efficacy, but there are several hurdles to overcome to achieve an effective tumor-specific systemic therapy. In this review, we have summarized the various strategies used to overcome the limitations of adenoviral-mediated gene delivery.

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

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Alemany R, Suzuki K, Curiel DT . Blood clearance rates of adenovirus type 5 in mice J Gen Virol 2000 81: 2605–2609

    Article  CAS  PubMed  Google Scholar 

  2. Tao N, Gao GP, Parr M et al. Sequestration of adenoviral vector by Kupffer cells leads to a nonlinear dose response of transduction in liver Mol Ther 2001 3: 28–35

    Article  CAS  PubMed  Google Scholar 

  3. Ye X, Jerebtsova M, Ray PE . Liver bypass significantly increases the transduction efficiency of recombinant adenoviral vectors in the lung, intestine, and kidney Hum Gene Ther 2000 11: 621–627

    Article  CAS  PubMed  Google Scholar 

  4. Vlachaki MT, Hernandez-Garcia A, Ittmann M et al. Impact of preimmunization on adenoviral vector expression and toxicity in a subcutaneous mouse cancer model Mol Ther 2002 6: 342–348

    Article  CAS  PubMed  Google Scholar 

  5. Bergelson JM, Cunningham JA, Droguett G et al. Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5 Science 1997 275: 1320–1323

    Article  CAS  PubMed  Google Scholar 

  6. Wickham TJ, Mathias P, Cheresh DA, Nemerow GR . Integrins alpha v beta 3 and alpha v beta 5 promote adenovirus internalisation but not virus attachment Cell 1993 73: 309–319

    Article  CAS  PubMed  Google Scholar 

  7. Dechecchi MC, Tamanini A, Bonizzato A, Cabrini G . Heparan sulfate glycosaminoglycans are involved in adenovirus type 5 and 2-host cell interactions Virology 2000 268: 382–390

    Article  CAS  PubMed  Google Scholar 

  8. Dechecchi MC, Melotti P, Bonizzato A, Santacatterina M, Chilosi M, Cabrini G . Heparan sulfate glycosaminoglycans are receptors sufficient to mediate the initial binding of adenovirus types 2 and 5 J Virol 2001 75: 8772–8780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bergelson JM, Krithivas A, Celi L et al. The murine CAR homolog is a receptor for coxsackie B viruses and adenoviruses J Virol 1998 72: 415–419

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Alemany R, Curiel DT . CAR-binding ablation does not change biodistribution and toxicity of adenoviral vectors Gene Ther 2001 8: 1347–1353

    Article  CAS  PubMed  Google Scholar 

  11. Leissner P, Legrand V, Schlesinger Y et al. Influence of adenoviral fiber mutations on viral encapsidation, infectivity and in vivo tropism Gene Ther 2001 8: 49–57

    Article  CAS  PubMed  Google Scholar 

  12. Smith T, Idamakanti N, Kylefjord H et al. In vivo hepatic adenoviral gene delivery occurs independently of the coxsackievirus–adenovirus receptor Mol Ther 2002 5: 770–779

    Article  CAS  PubMed  Google Scholar 

  13. Einfeld DA, Schroeder R, Roelvink PW et al. Reducing the native tropism of adenovirus vectors requires removal of both CAR and integrin interactions J Virol 2001 75: 11284–11291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Douglas JT, Rogers BE, Rosenfeld ME, Michael SI, Feng M, Curiel DT . Targeted gene delivery by tropism-modified adenoviral vectors Nat Biotechnol 1996 14: 1574–1578

    Article  CAS  PubMed  Google Scholar 

  15. Wickham TJ, Lee GM, Titus JA et al. Targeted adenovirus-mediated gene delivery to T cells via CD3 J Virol 1997 71: 7663–7669

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Wickham TJ, Haskard D, Segal D, Kovesdi I . Targeting endothelium for gene therapy via receptors up-regulated during angiogenesis and inflammation Cancer Immunol Immunother 1997 45: 149–151

    Article  CAS  PubMed  Google Scholar 

  17. Goldman CK, Rogers BE, Douglas JT et al. Targeted gene delivery to Kaposi's sarcoma cells via the fibroblast growth factor receptor Cancer Res 1997 57: 1447–1451

    CAS  PubMed  Google Scholar 

  18. Rancourt C, Rogers BE, Sosnowski BA et al. Basic fibroblast growth factor enhancement of adenovirus-mediated delivery of the herpes simplex virus thymidine kinase gene results in augmented therapeutic benefit in a murine model of ovarian cancer Clin Cancer Res 1998 4: 2455–2461

    CAS  PubMed  Google Scholar 

  19. Blackwell JL, Miller CR, Douglas JT et al. Retargeting to EGFR enhances adenovirus infection efficiency of squamous cell carcinoma Arch Otolaryngol Head Neck Surg 1999 125: 856–863

    Article  CAS  PubMed  Google Scholar 

  20. Nicklin SA, White SJ, Watkins SJ, Hawkins RE, Baker AH . Selective targeting of gene transfer to vascular endothelial cells by use of peptides isolated by phage display Circulation 2000 102: 231–237

    Article  CAS  PubMed  Google Scholar 

  21. McDonald GA, Zhu G, Li Y, Kovesdi I, Wickham TJ, Sukhatme VP . Efficient adenoviral gene transfer to kidney cortical vasculature utilizing a fiber modified vector J Gene Med 1999 1: 103–110

    Article  CAS  PubMed  Google Scholar 

  22. Kasono K, Blackwell JL, Douglas JT et al. Selective gene delivery to head and neck cancer cells via an integrin targeted adenoviral vector Clin Cancer Res 1999 5: 2571–2579

    CAS  PubMed  Google Scholar 

  23. Vanderkwaak TJ, Wang M, Gomez-Navarro J et al. An advanced generation of adenoviral vectors selectively enhances gene transfer for ovarian cancer gene therapy approaches Gynecol Oncol 1999 74: 227–234

    Article  CAS  PubMed  Google Scholar 

  24. Printz MA, Gonzalez AM, Cunningham M et al. Fibroblast growth factor 2–retargeted adenoviral vectors exhibit a modified biolocalization pattern and display reduced toxicity relative to native adenoviral vectors Hum Gene Ther 2000 11: 191–204

    Article  CAS  PubMed  Google Scholar 

  25. Reynolds PN, Zinn KR, Gavrilyuk VD et al. A targetable, injectable adenoviral vector for selective gene delivery to pulmonary endothelium in vivo Mol Ther 2000 2: 562–578

    Article  CAS  PubMed  Google Scholar 

  26. Romanczuk H, Galer CE, Zabner J, Barsomian G, Wadsworth SC, O'Riordan CR . Modification of an adenoviral vector with biologically selected peptides: a novel strategy for gene delivery to cells of choice Hum Gene Ther 1999 10: 2615–2626

    Article  CAS  PubMed  Google Scholar 

  27. Drapkin PT, O'Riordan CR, Yi SM et al. Targeting the urokinase plasminogen activator receptor enhances gene transfer to human airway epithelia J Clin Invest 2000 105: 589–596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Fisher KD, Stallwood Y, Green NK, Ulbrich K, Mautner V, Seymour LW . Polymer-coated adenovirus permits efficient retargeting and evades neutralising antibodies Gene Ther 2001 8: 341–348

    Article  CAS  PubMed  Google Scholar 

  29. Green NK, Hale SJ, Fasci CA, Fisher KD, Mautner V, Seymour LW . Polymer modification of adenoviral vectors for systemic gene delivery J Gene Med 2001 (published abstracts from the 9th meeting of the European Society for Gene Therapy)

  30. Barker DD, Berk AJ . Adenovirus proteins from both E1B reading frames are required for transformation of rodent cells by viral infection and DNA transfection Virology 1987 156: 107–121

    Article  CAS  PubMed  Google Scholar 

  31. Bischoff JR, Kirn DH, Williams A et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells Science 1996 274: 373–376

    Article  CAS  PubMed  Google Scholar 

  32. Goodrum FD, Ornelles DA . p53 status does not determine outcome of E1B 55-kilodalton mutant adenovirus lytic infection J Virol 1998 72: 9479–9490

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Rothman T, Hengstermann A, Whitaker NJ, Scheffner M, zur Hausen H . Replication of ONYX-015, a potential anticancer adenovirus, is independent of p53 status in tumor cells J Virol 1998 72: 9470–9478

    Google Scholar 

  34. Turnell AS, Grand RJ, Gallimore PH . The replicative capacities of large E1B-null group A and group C adenoviruses are independent of host cell p53 status J Virol 1999 73: 2074–2083

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Bates S, Phillips AC, Clark PA et al. p14ARF links the tumour suppressors RB and p53 Nature 1998 395: 124–125

    Article  CAS  PubMed  Google Scholar 

  36. Sherr CJ, Weber JD . The ARF/p53 pathway Curr Opin Genet Dev 2000 10: 94–99

    Article  CAS  PubMed  Google Scholar 

  37. Ries SJ, Brandts CH, Chung AS et al. Loss of p14ARF in tumor cells facilitates replication of the adenovirus mutant dl1520 (ONYX-015) Nat Med 2000 6: 1128–1133

    Article  CAS  PubMed  Google Scholar 

  38. Doronin K, Toth K, Kuppuswamy M, Ward P, Tollefson AE, Wold WS . Tumor-specific, replication-competent adenovirus vectors overexpressing the adenovirus death protein J Virol 2000 74: 6147–6155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bohinski RJ, Di Lauro R, Whitsett JA . The lung-specific surfactant protein B gene promoter is a target for thyroid transcription factor 1 and hepatocyte nuclear factor 3, indicating common factors for organ-specific gene expression along the foregut axis Mol Cell Biol September 1994 14: 5671–5681

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Doronin K, Kuppuswamy M, Toth K et al. Tissue-specific, tumor-selective, replication-competent adenovirus vector for cancer gene therapy J Virol 2001 75: 3314–3324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Habib NA, Mitry R, Seth P et al. Adenovirus replication-competent vectors (KD1, KD3) complement the cytotoxicity and transgene expression from replication-defective vectors (Ad-GFP, Ad-Luc) Cancer Gene Ther 2002 9: 651–654

    Article  CAS  PubMed  Google Scholar 

  42. Jelsma TN, Howe JA, Mymryk JS, Evelegh CM, Cunniff NF, Bayley ST . Sequences in E1A proteins of human adenovirus 5 required for cell transformation, repression of a transcriptional enhancer, and induction of proliferating cell nuclear antigen Virology 1989 171: 120–130

    Article  CAS  PubMed  Google Scholar 

  43. Fueyo J, Gomez-Manzano C, Alemany R . A mutant oncolytic adenovirus targeting the Rb pathway produces anti-glioma effect in vivo Oncogene 2000 19: 2–12

    Article  CAS  PubMed  Google Scholar 

  44. Heise C, Hermiston T, Johnson L et al. An adenovirus E1A mutant that demonstrates potent and selective systemic anti-tumoral efficacy Nat Med 2000 6: 1134–1139

    Article  CAS  PubMed  Google Scholar 

  45. Rodriguez R, Schuur ER, Lim HY, Henderson GA, Simons JW, Henderson DR . Prostate attenuated replication competent adenovirus (ARCA) CN706: a selective cytotoxic for prostate-specific antigen-positive prostate cancer cells Cancer Res 1997 57: 2559–2563

    CAS  PubMed  Google Scholar 

  46. Simons JW, Mikhak B, Van Der Poel HG et al. Molecular and clinical activity of CN706, a PSA-selective oncolytic AD5 vector in a phase I trial in locally recurrent prostate cancer following radiation therapy Mol Ther 2000 1: S144–S145

    Article  Google Scholar 

  47. Hallenbeck PL, Chang YN, Hay C et al. A novel tumor-specific replication-restricted adenoviral vector for gene therapy of hepatocellular carcinoma Hum Gene Ther 1999 10: 1721–1733

    Article  CAS  PubMed  Google Scholar 

  48. Kurihara T, Brough DE, Kovesdi I, Kufe DW . Selectivity of a replication-competent adenovirus for human breast carcinoma cells expressing the MUC1 antigen J Clin Invest 2000 106: 763–771

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ganly I, Kirn D, Eckhardt SG et al. A phase I study of Onyx-015, an E1B attenuated adenovirus, administered intratumourally to patients with recurrent head and neck cancer Clin Cancer Res 2000 6: 798–806

    CAS  PubMed  Google Scholar 

  50. Mulvihill S, Warren R, Venook A et al. Safety and feasibility of injection with an E1B–55 kDa gene–deleted, replication-selective adenovirus (ONYX-015) into primary carcinomas of the pancreas: a phase I trial Gene Ther 2001 8: 308–315

    Article  CAS  PubMed  Google Scholar 

  51. Batshaw ML, Wilson JM, Raper S, Yudkoff M, Robinson MB . Recombinant adenovirus gene transfer in adults with partial ornithine transcarbamylase deficiency (OTCD) Hum Gene Ther 1999 10: 2419–2437

    Article  CAS  PubMed  Google Scholar 

  52. Miller D . Gene therapy on trial Science 2000 288: 951–957

    Article  Google Scholar 

  53. Zhang Y, Chirmule N, Gao GP et al. Acute cytokine response to systemic adenoviral vectors in mice is mediated by dendritic cells and macrophages Mol Ther 2001 3: 697–707

    Article  CAS  PubMed  Google Scholar 

  54. Yang Y, Jooss KU, Su Q, Ertl HC, Wilson JM . Immune responses to viral antigens versus transgene product in the elimination of recombinant adenovirus-infected hepatocytes in vivo Gene Ther 1996 3: 137–144

    PubMed  Google Scholar 

  55. Yang Y, Wilson JM . Clearance of adenovirus-infected hepatocytes by MHC class I–restricted CD4+ CTLs in vivo J Immunol 1995 155: 2564–2570

    CAS  PubMed  Google Scholar 

  56. Cichon G, Boeckh-Herwig S, Schmidt HH et al. Complement activation by recombinant adenoviruses Gene Ther 2001 8: 1794–1800

    Article  CAS  PubMed  Google Scholar 

  57. Reid T, Galanis E, Abbruzzese J et al. Intra-arterial administration of a replication-selective adenovirus (dl1520) in patients with colorectal carcinoma metastatic to the liver: a phase I trial Gene Ther 2001 8: 1618–1626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Nemunaitis J, Cunningham C, Buchanan A et al. Intravenous infusion of a replication-selective adenovirus (ONYX-015) in cancer patients: safety, feasibility and biological activity Gene Ther 2001 8: 746–759

    Article  CAS  PubMed  Google Scholar 

  59. Wildner O, Morris JC, Vahanian NN, Ford H Jr, Ramsey WJ, Blaese RM . Adenoviral vectors capable of replication improve the efficacy of HSVtk/GCV suicide gene therapy of cancer Gene Ther 1999 6: 57–62

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to Cancer Research UK and to Hybrid Systems for financial support.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Nicola K Green.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Green, N., Seymour, L. Adenoviral vectors: Systemic delivery and tumor targeting. Cancer Gene Ther 9, 1036–1042 (2002). https://doi.org/10.1038/sj.cgt.7700541

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7700541

Keywords

This article is cited by

Search

Quick links