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.

  • Millennium Review
  • Published:

Cancer gene therapy: hard lessons and new courses

Gene Therapy volume 7, pages 2–8 (2000)Cite this article

Abstract

Gene therapy for the treatment of cancer was initiated with high levels of optimism and enthusiasm. Recently, this perception has had to be tempered by the realisation that efficiency and accuracy of gene delivery remain the most significant barriers to its success. So far, there has been a disappointing inability to reach target cells with sufficient efficacy to generate high enough levels of direct killing and this has necessitated the invocation of bystander effects in order for any potential strategy to be convincing. At least in the foreseeable future, clinical advance will come from co-operation with other more established disciplines – such as chemotherapy, radiotherapy and immunotherapy. This is inevitable – and necessary – in order to prove that gene therapy can have efficacy as part of a combinatorial therapy, before hoping to move clinical mountains alone. In addition, there will have to be a thorough understanding of the clinical situations in which gene therapy will be used in order both to understand its own limitations, and to exploit its full potential. This will enable it to find the appropriate clinical niche in which its abilities will be optimally useful. Finally, anyone wishing to practise clinical cancer gene therapy will rapidly have to learn the ways of the free market and be able to juggle commercial necessities with ideological purity.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Plautz GE et al. Immunotherapy of malignancy by in vivo gene transfer into tumors Proc Natl Acad Sci USA 1993 90: 4645–4649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ram Z et al. Therapy of malignant brain tumors by intratumoral implantation of retroviral vector-producing cells Nature Med 1997 3: 1354–1361

    Article  CAS  PubMed  Google Scholar 

  3. Soiffer R et al. Vaccination with irradiated autologous melanoma cells engineered to secrete human granulocyte–macrophage colony-stimulating factor generates potent antitumor immunity in patients with metastatic melanoma Proc Natl Acad Sci USA 1998 95: 13141–13146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Palu G et al. Gene therapy of glioblastoma multiforme via combined expression of suicide and cytokine genes: a pilot study in humans Gene Therapy 1999 6: 330–337

    Article  CAS  PubMed  Google Scholar 

  5. Roth JA et al. Retrovirus-mediated wild-type p53 gene transfer to tumors of patients with lung cancer Nature Med 1996 2: 985–991.

    Article  CAS  PubMed  Google Scholar 

  6. Heise C et al. ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents Nature Med 1999 3: 639–645

    Article  Google Scholar 

  7. Peng K-W, Vile R . Vector development for cancer gene therapy Tumor Targeting 1999 4: 3–11

    CAS  Google Scholar 

  8. Verma I, Somia N . Gene therapy – promises, problems and prospects Nature 1997 389: 239–242

    Article  CAS  PubMed  Google Scholar 

  9. Moolten FL . Drug sensitivity (‘suicide’) genes for selective cancer chemotherapy Cancer Gene Ther 1994 1: 279–287

    CAS  PubMed  Google Scholar 

  10. Pardoll DM . Paracrine cytokine adjuvants in cancer immunotherapy Annu Rev Immunol 1995 13: 399–415

    Article  CAS  PubMed  Google Scholar 

  11. Bischoff J et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells Science 1996 274: 373–376

    Article  CAS  PubMed  Google Scholar 

  12. Marcelli M et al. Signaling pathway activated during apoptosis of the prostate cancer cell line LNCaP: overexpression of caspase-7 as a new gene therapy strategy for prostate cancer Cancer Res 1999 59: 382–390

    CAS  PubMed  Google Scholar 

  13. Yu JS et al. Retroviral delivery and tetracycline-dependent expression of IL-1beta-converting enzyme (ICE) in a rate glioma model provides controlled induction of apoptotic death in tumor cells Cancer Res 1996 56: 5423–5427

    CAS  PubMed  Google Scholar 

  14. Marte BM, Downward J . PKB/Akt: connecting phosphoinositide 3-kinase to cell survival and beyond Trends Biochem Sci 1997 22: 355–358

    Article  CAS  PubMed  Google Scholar 

  15. Khwaja A et al. Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway EMBO J 1997 16: 2783–2793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Freeman SM, Ramesh R, Marrogi AJ . Immune system in suicide gene therapy Lancet 1997 349: 2–3

    Article  CAS  PubMed  Google Scholar 

  17. Vile RG 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 1997 71: 267–274

    Article  CAS  PubMed  Google Scholar 

  18. Bouvet M et al. Adenovirus-mediated wild-type p53 gene transfer down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in human colon cancer Cancer Res 1998 58: 2288–2292

    CAS  PubMed  Google Scholar 

  19. Liu Y et al. Systemic gene delivery expands the repertoire of effective antiangiogenic agents J Biol Chem 1999 274: 13338–13344.

    Article  CAS  PubMed  Google Scholar 

  20. Frank DK, Frederick MJ, Liu TJ, Clayman GL . Bystander effect in the adenovirus-mediated wild-type p53 gene therapy model of human squamous cell carcinoma of the head and neck Clin Cancer Res 1998 4: 2521–2528

    CAS  PubMed  Google Scholar 

  21. Touraine RL, Ishii-Morita H, Ramsey WJ, Blaese RM . The bystander effect in the HSVtk/ganciclovir system and its relationship to gap junctional communication Gene Therapy 1998 5: 1705–1711

    Article  CAS  PubMed  Google Scholar 

  22. Colombo MP, Modesti A, Parmiani G, Forni G . Local cytokine availability elicits tumor rejection and systemic immunity through granulocyte-T-lymphocyte cross-talk Cancer Res 1992 52: 4853–4857

    CAS  PubMed  Google Scholar 

  23. Melcher AA et al. Tumor immunogenicity is determined by the mechanism of cell death via induction of heat shock protein expression Nature Med 1998 4: 581–587

    Article  CAS  PubMed  Google Scholar 

  24. Castleden SA et al. A family of bicistronic vectors to enhance both local and systemic anti-tumour effects of HSVtk or cytokine expression in a murine melanoma model Hum Gene Ther 1997 8: 2087–2102

    Article  CAS  PubMed  Google Scholar 

  25. Mullen CA, Coale MM, Lowe R, Blaese RM . Tumors expressing the cytosine deaminase suicide gene can be eliminated in vivo with 5-fluorocytosine and induce protective immunity to wild type tumor Cancer Res 1994 54: 1503–1506

    CAS  PubMed  Google Scholar 

  26. Matzinger P . An innate sense of danger Semin Immunol 1998 10: 399–415

    Article  CAS  PubMed  Google Scholar 

  27. Melcher AA, Gough MJ, Todryk S, Vile RG . Apoptosis or necrosis for tumour immunotherapy – what's in a name? J Mol Med 1999 (in press)

  28. Kokoris MS, Sabo P, Adman ET, Black ME . Enhancement of tumor ablation by a selected HSV-1 thymidine kinase mutant Gene Therapy 1999 6: 1415–1426

    Article  CAS  PubMed  Google Scholar 

  29. Ali M, Lemoine NR, Ring CJA . The use of DNA viruses as vectors for gene therapy Gene Therapy 1994 1: 367–384

    CAS  PubMed  Google Scholar 

  30. Todryk S et al. Disabled infectious single-cycle herpes simplex virus vector for immunotherapy of colorectal cancer Hum Gene Ther 1999 (in press)

  31. Russell SJ . Replicating vectors for cancer therapy: a question of strategy Sem Cancer Biol 1994 5: 437–443

    CAS  Google Scholar 

  32. Hall AR, Dix BR, O'Carroll SJ, Braithwaite AW . p53-dependent cell death/apoptosis is required for a productive adenovirus infection Nature Med 1998 4: 1068–1072

    Article  CAS  PubMed  Google Scholar 

  33. Wildner O, Blaese RM, Morris JC . Therapy of colon cancer with oncolytic adenovirus is enhanced by the addition of Herpes simplex virus-thymidine kinase Cancer Res 1999 59: 410–413

    CAS  PubMed  Google Scholar 

  34. Coffey MC, Strong JE, Forsyth PA, Lee PWK . Reovirus therapy of tumors with activated Ras pathway Science 1998 282: 1332–1334

    Article  CAS  PubMed  Google Scholar 

  35. Rodriguez R et al. 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 

  36. Vassaux G, Hurst HC, Lemoine NR . Insulation of a tumour-selective conditional expression cassette in an adenoviral vector Gene Therapy 1999 6: 1192–1197

    Article  CAS  PubMed  Google Scholar 

  37. Vile RG, Sunassee K, Diaz RM . Strategies for achieving multiple layers of selectivity in gene therapy Mol Med Today 1998 4: 84–92

    Article  CAS  PubMed  Google Scholar 

  38. Feng M et al. Stable in vivo transduction via a novel adenoviral/retroviral chimeric vector Nat Biotechnol 1997 15: 866–870

    Article  CAS  PubMed  Google Scholar 

  39. Tan BT, Wu L, Berk AJ . An adenovirus–Epstein Barr virus hybrid vector that stably transforms cultured cells with high efficiency J Virol 1999 73: 7582–7589

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Elliot G, O'Hare P . Intercellular trafficking and protein delivery by a Herpesvirus structural protein Cell 1997 88: 1–20

    Article  Google Scholar 

  41. Peng KW, Vile RG, Cosset FL, Russell SJ . Selective transduction of protease rich tumors by matrix-metalloproteinase-targeted retroviral vectors Gene Therapy 1999 6: 1552–1557

    Article  CAS  PubMed  Google Scholar 

  42. Haisma HJ et al. Tumor-specific gene transfer via an adenoviral vector targeted to the pan-carcinoma antigen EpCAM Gene Therapy 1999 6: 1469–1474

    Article  CAS  PubMed  Google Scholar 

  43. Koivunen E et al. Tumor targeting with a selective gelatinase inhibitor Nat Biotechnol 1999 17: 768–774

    Article  CAS  PubMed  Google Scholar 

  44. Miller N, Whelan J . Progress in transcriptionally targeted and regulatable vectors for genetic therapy Hum Gene Ther 1997 8: 803–815

    Article  CAS  PubMed  Google Scholar 

  45. Taniguchi T, Rigg A, Lemoine NR . Targeting angiogenesis: genetic intervention which strikes at the weak link of tumorigenesis Gene Therapy 1998 5: 1011–1013

    Article  CAS  PubMed  Google Scholar 

  46. Li H et al. Adenovirus-mediated delivery of a uPA/uPAR antagonist suppresses angiogenesis-dependent tumor growth and dissemination in mice Gene Therapy 1998 5: 1105–1113

    Article  CAS  PubMed  Google Scholar 

  47. Nguyen JT et al. Adeno-associated virus-mediated delivery of antiangiogenic factors as an antitumor strategy Cancer Res 1998 58: 5673–5677

    CAS  PubMed  Google Scholar 

  48. Tanaka T, Cao Y, Folkman J, Fine HA . Viral vector-targeted antiangiogenic gene therapy utilizing an angiostatin complementary DNA Cancer Res 1998 58: 3362–3369

    CAS  PubMed  Google Scholar 

  49. Cao Y et al. Expression of angiostatin cDNA in a murine fibrosarcoma suppresses primary tumor growth and produces long-term dormancy of metastases J Clin Invest 1998 101: 1055–1063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Blezinger P et al. Systemic inhibition of tumor growth and tumor metastases by intramuscular administration of the endostatin gene Nat Biotechnol 1999 17: 343–348

    Article  CAS  PubMed  Google Scholar 

  51. Hock H et al. Vaccinations with tumor cells genetically engineered to produce different cytokines: effectivity not superior to a classical adjuvant Cancer Res 1993 53: 714–716

    CAS  PubMed  Google Scholar 

  52. Dranoff G et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte macrophage colony stimulating factor stimulates potent, specific, and long lasting anti-tumor immunity Proc Natl Acad Sci USA 1993 90: 3539–3543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Cavallo F et al. Immune events associated with the cure of established tumors and spontaneous metastases by local and systemic interleukin 12 Cancer Res 1999 59: 414–421

    CAS  PubMed  Google Scholar 

  54. Boon T, van der Bruggen P . Human tumor antigens recognized by T lymphocytes J Exp Med 1996 183: 725–729

    Article  CAS  PubMed  Google Scholar 

  55. Wang R-F et al. Cloning genes encoding MHC class II-restricted antigens: mutated CDC27 as a tumor antigen Science 1999 284: 1351–1354

    Article  CAS  PubMed  Google Scholar 

  56. Wang R-F, Wang X, Rosenberg SA . Identification of a novel major histocompatibility complex class II-restricted tumor antigen resulting from a chromosomal rearrangement recognized by CD4+ T cells J Exp Med 1999 189: 1659–1668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Mayordomo JI et al. Bone marrow-derived dendritic cells pulsed with synthetic tumour pepiteds elicit protective and therapeutic antitumour immunity Nature Med 1995 1: 1297–1302

    Article  CAS  PubMed  Google Scholar 

  58. Melcher A et al. Adoptive transfer of immature dendritic cells with autologous or allogeneic tumor cells generates systemic antitumor immunity Cancer Res 1999 59: 2802–2805

    CAS  PubMed  Google Scholar 

  59. Albert ML, Sauter B, Bhardwaj N . Dendritic cells acquire antigen from apoptotic cells and induce class I-restriected CTLs Nature 1998 392: 86–89

    Article  CAS  PubMed  Google Scholar 

  60. Banchereau J, Steinman RM . Dendritic cells and the control of immunity Nature 1998 392: 245–252

    Article  CAS  PubMed  Google Scholar 

  61. Huang AYC et al. Role of bone marrow derived cells in presenting MHC class I-restricted tumor antigens Science 1994 264: 961–965

    Article  CAS  PubMed  Google Scholar 

  62. Vile RG, Chong H . Immunotherapy: combinatorial molecular immunotherapy – a synthesis and suggestions Cancer Metastasis Rev 1996 15: 351–364

    Article  CAS  PubMed  Google Scholar 

  63. Overwijk WW et al. Vaccination with a recombinant vaccinia virus encoding a self antigen induced autoimmune vitiligo and tumor cell destruction in mice: requirement for CD4+ T lymphocytes Proc Natl Acad Sci USA 1999 96: 2982–2987

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Houghton AN . Cancer antigens: immune recognition of self and altered self J Exp Med 1994 180: 1–4

    Article  CAS  PubMed  Google Scholar 

  65. Parmiani G . Tumor immunity as autoimmunity: tumor antigens include normal self proteins which stimulate anergic peripheral T cells Immunol Today 1993 14: 536–538

    Article  CAS  PubMed  Google Scholar 

  66. Pardoll DM . Inducing autoimmune disease to treat cancer Proc Natl Acad Sci USA 1999 96: 5340–5342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Melcher AA, Garcia-Ribas I, Vile RG . Gene therapy for cancer – managing expectations Br Med J 1997 315: 1604–1607

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Molecular Medicine Program, Guggenheim 18, Mayo Clinic, 200 First Street SW, Rochester, 55905, Minnesota, USA

    R G Vile & S J Russell

  2. Department of Cancer Medicine, ICRF Molecular Oncology Unit, Imperial College School of Medicine, London, UK

    N R Lemoine

Authors
  1. R G Vile
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S J Russell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N R Lemoine
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vile, R., Russell, S. & Lemoine, N. Cancer gene therapy: hard lessons and new courses. Gene Ther 7, 2–8 (2000). https://doi.org/10.1038/sj.gt.3301084

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3301084

Keywords

This article is cited by

Search

Advanced search

Quick links