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.

  • Perspective
  • Published:

Gene manipulation in the induction of anti-tumour immunity

Gene Therapy volume 6, pages 1796–1797 (1999)Cite this article

Immune responses to tumour cells are frequently absent or ineffective in human cancers. A major challenge in basic and clinical cancer research is to design rational cancer vaccines which bypass or overcome the obstacles that the tumour microenvironment presents to an effective immune response. Although an antibody response may sometimes be helpful, most effective antitumour immune responses in animal models are mediated by cytotoxic T cells (CTL). Tumours may fail to prime a CTL response and/or may evade effector mechanisms. Genetic manipulation of tumour or immune cells can therefore be used to overcome a ‘block’ at one or more of the steps necessary for generation of a T cell response – presentation, costimulation, CTL expansion (including provision of adequate T cell help) and effective cytotoxicity. Within the past 10 years, numerous such gene therapy strategies have been validated in animal models. Many have reached the clinical trial stage, particularly in cancers such as melanoma and renal carcinoma, which were already known to respond in some cases to non-gene-based immunotherapies.

Initial approaches concentrated on strategies designed to enhance the capacity of tumour cells to activate T cells directly and centered on transduction of tumour cells with T cell-stimulating cytokines.1 In several animal models, vaccination with cytokine-transduced tumour cells induced rejection of the transduced tumours and, in some cases, protection against re-challenge with the parental tumour. Protective CTL-based immunity conferred by IL-2-transfected tumour cells was interpreted as due to bypassing of the CTL requirements for paracrine IL-2 production by T helper (Th) cells.2 Interferon-γ (IFNγ) and IL-12 transfection, with the aim of biasing towards a Th1-like response, was also successful in animal tumour vaccination models, presumably by favouring cell-mediated immunity. Ex vivo transfection of tumour cells with DNA for the above cytokines has since been shown to be feasible and tolerated in clinical trials (reviewed in Ref. 3). The early success of cytokine transduction in animal studies prompted the systematic evaluation of the relative efficacy of tumour cytokine transfection with a range of cytokines in a variety of tumour models.4 This work showed that GM-CSF appeared to be the most efficacious of 10 cytokines tested and clinical trials of vaccination with autologous tumour transduced with GM-CSF have already been performed.5

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

References

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

    Article  Google Scholar 

  2. ER Fearon et al. Interleukin-2 production by tumor cells bypasses T helper function in the generation of an antitumor response Cell 1990 60: 397–403

    Article  Google Scholar 

  3. JW Simons, B Mikhak . Ex-vivo gene therapy using cytokine-transduced tumor vaccines: molecular and clinical pharmacology Semin Oncol 1998 25: 661–676

    Google Scholar 

  4. G Dranoff 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  Google Scholar 

  5. R Soiffer 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  Google Scholar 

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

    Article  Google Scholar 

  7. S Fujii et al. Activated dendritic cells from bone marrow cells of mice receiving cytokine-expressing tumor cells are associated with the enhanced survival of mice bearing syngeneic tumors Blood 1999 93: 4328–4335

    Google Scholar 

  8. C Chiodoni et al. Dendritic cells infiltrating tumors cotransduced with granulocyte/macrophage colony-stimulating factor (GM-CSF) and CD40 ligand genes take up and present endogenous tumor-associated antigens, and prime naive mice for a cytotoxic T lymphocyte response J Exp Med 1999 190: 125–133

    Article  Google Scholar 

  9. SE Townsend, JP Allison . Tumor rejection after direct costimulation of CD8+ T cells by B7-transfected melanoma cells Science 1993 259: 368–370

    Article  Google Scholar 

  10. AY Huang, AT Bruce, DM Pardoll, HI Levitsky . Does B7–1 expression confer antigen-presenting cell capacity to tumors in vivo? J Exp Med 1996 183: 769–776

    Article  Google Scholar 

  11. JR Kanwar, RW Berg, K Lehnert, GW Krissansen . Taking lessons from dendritic cells: multiple xenogeneic ligands for leukocyte integrins have the potential to stimulate antitumor immunity Gene Therapy 1999 6: 1835–1844

    Article  Google Scholar 

  12. A Porgador, D Snyder, E Gilboa . Induction of antitumor immunity using bone marrow-generated dendritic cells J Immunol 1996 156: 2918–2926

    Google Scholar 

  13. CM Celluzzi et al. Peptide-pulsed dendritic cells induce antigen-specific CTL-mediated protective tumor immunity J Exp Med 1996 183: 283–287

    Article  Google Scholar 

  14. FO Nestle et al. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells Nat Med 1998 4: 328–332

    Article  Google Scholar 

  15. AM Sponaas, C Carstens, N Koch . C-terminal extension of the MHC class II-associated invariant chain by an antigenic sequence triggers activation of naive T cells Gene Therapy 1999 6: 1826–1834

    Article  Google Scholar 

  16. K Hung et al. The central role of CD4(+) T cells in the antitumor immune response J Exp Med 1998 188: 2357–2368

    Article  Google Scholar 

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

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Imperial Cancer Research Fund, Cancer Medicine Reesearch Unit, St James’ Hospital, Leeds, UK

    D M O’Donnell & P M Patel

  2. Immunobiology Laboratory, Imperial Cancer Research Fund, London, UK

    C Reis e Sousa

Authors
  1. D M O’Donnell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P M Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C Reis e Sousa
    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

O’Donnell, D., Patel, P. & e Sousa, C. Gene manipulation in the induction of anti-tumour immunity. Gene Ther 6, 1796–1797 (1999). https://doi.org/10.1038/sj.gt.3301073

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3301073

Search

Advanced search

Quick links