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.

  • Original Article
  • Published:

Intratumoral injection of IL-secreting syngeneic/allogeneic fibroblasts transfected with DNA from breast cancer cells prolongs the survival of mice with intracerebral breast cancer

Cancer Gene Therapy volume 12, pages 708–714 (2005)Cite this article

Abstract

Prior studies have revealed the immunotherapeutic properties of a vaccine prepared by transfer of genomic DNA from breast cancer cells into a highly immunogenic cell line. The rationale for this type of vaccine is that genes specifying an array of weakly immunogenic, unique tumor antigens associated with the malignant cells will be expressed in a highly immunogenic form by the transfected cells. Here, the immunotherapeutic properties of a vaccine prepared by transfection of mouse fibroblasts with DNA from a breast carcinoma (SB-5b) that arose spontaneously in a C3H/He mouse (H-2Kb) were tested in mice with intracerebral breast cancer. To augment their nonspecific immunogenic properties, before DNA transfer, the fibroblasts (of C3H/He mouse origin) were modified to express allogeneic MHC class I H-2Kb-determinants and to secrete IL-2, IL-18 or GM-CSF. The results indicate that C3H/He mice injected intracerebrally (i.c.) with the breast cancer cells and syngeneic/allogeneic-transfected fibroblasts modified to secrete IL-2 survived significantly longer (P<.005) than mice in various control groups, including mice injected i.c. with the breast cancer cells alone. The immunotherapeutic properties of transfected fibroblasts modified to secrete IL-18 or GM-CSF were less efficacious. The results of two independent in vitro cytotoxicity assays indicate that systemic cellular antitumor immunity was generated in mice injected i.c. with the transfected cells, and the immunity was mediated predominantly by CD8+ T cells.

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
Figure 4

Similar content being viewed by others

References

  1. Ogura M, Mitsumori M, Okumura S, et al. Radiation therapy for brain metastases from breast cancer. Breast Cancer. 2003;10:349–355.

    Article  PubMed  Google Scholar 

  2. Bendell JC, Domchek SM, Burstein HJ, et al. Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer. 2003;97:2972–2977.

    Article  PubMed  Google Scholar 

  3. Sampath P, Hanes J, Dimeco F, et al. Paracrine immunotherapy with interleukin-2 and local chemotherapy is synergistic in the treatment of experimental brain tumors. Cancer Res. 1999;59:2107–2114.

    CAS  PubMed  Google Scholar 

  4. Dranoff G . Cancer gene therapy: connecting basic research with clinical inquiry. J Clin Oncol. 1998;16:2548–2556.

    Article  CAS  PubMed  Google Scholar 

  5. Dranoff G . The use of gene transfer in cancer immunotherapy. Forum. 1998;8:357–364.

    CAS  PubMed  Google Scholar 

  6. Horton HM, Anderson D, Hernandez P, Barnhart KM, Norman JA, Parker SE . A gene therapy for cancer using intramuscular injection of plasmid DNA encoding interferon alpha. Proc Natl Acad Sci USA. 1999;96:1553–1558.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hiroishi K, Tuting T, Tahara H, Lotze MT . Interferon-alpha gene therapy in combination with CD80 transduction reduces tumorigenecity and growth of established tumor in poorly immunogenic tumor models. Gene Therapy. 1999;6:1988–1994.

    Article  CAS  PubMed  Google Scholar 

  8. Ferrantini M, Giovarelli M, Modesti A, et al. IFN-alpha 1 gene expression into metastatic murine adenocarcinoma (TS/A) results in CD8+ T cell-mediated tumor rejection and development of antitumor immunity. Comparative studies with IFN-gamma-producing TS/A cells. J Immunol. 1994;153:4604–4615.

    CAS  PubMed  Google Scholar 

  9. Yu JS, Wei MX, Chiocca EA, Martuza RL, Tepper RI . Treatment of glioma by engineered interleukin 4-secreting cells. Cancer Res. 1993;53:3125–3128.

    CAS  PubMed  Google Scholar 

  10. Zitvogel L, Tahara H, Robbins PD, et al. Cancer immunotherapy of established tumors with IL-12. Effective delivery by genetically engineered fibroblasts. J Immunol. 1995;155:1393–1403.

    CAS  PubMed  Google Scholar 

  11. Osaki T, Hashimoto W, Gambotto A, et al. Potent antitumor effects mediated by local expression of the mature form of the interferon-gamma inducing factor, interleukin-18 (IL-18). Gene Therapy. 1999;6:808–815.

    Article  CAS  PubMed  Google Scholar 

  12. Lo CH, Lee SC, Wu PY, et al. Antitumor and antimetastatic activity of IL-23. J Immunol. 2003;171:600–607.

    Article  CAS  PubMed  Google Scholar 

  13. Disis M, Cheever MA . HER-Z/neu protein: a target for antigen-specific immunotherapy of human cancer. Adv Cancer Res. 1997;71:343–371.

    Article  CAS  PubMed  Google Scholar 

  14. de Zoeten E, Carr-Brendel V, Markovic D, Taylor-Papadimitriou J, Cohen EP . Treatment of breast cancer with fibroblasts transfected with DNA from breast cancer cells. J Immunol. 1999;162:6934–6941.

    CAS  PubMed  Google Scholar 

  15. Kim TS, Russell SJ, Collins MK, Cohen EP . Immunity to B 16 melanoma in mice immunized with IL-2- secreting allogeneic mouse fibroblasts expressing melanoma-associated antigens. Int J Cancer. 1992;51:283–289.

    Article  CAS  PubMed  Google Scholar 

  16. Yamada G, Kitamura Y, Sonoda H, et al. Retroviral expression of the human IL-2 gene in a murine T cell line results in a cell growth autonomy and tumorigenicity. EMBO J. 1987;6:2705–2709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cobere-Garapin F, Horodniceanu F, Kourilsky P, Garapin A . A new dominant hybrid selective marker for eucaryotic cells. J Mol Biol. 1981;150:1–14.

    Article  Google Scholar 

  18. Wigler M, Pellicer A, Silverstein S, Axel R, Urlaub G, Chasin L . DNA-mediated transfer of the adenine phosphoribosyltransferase locus into mammalian cells. Proc Natl Acad Sci USA. 1979;76:1373–1376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kim TS, Cohen EP . Interleukin-2-secreting mouse fibroblasts transfected with genomic DNA from murine melanoma cells prolong the survival of mice with melanoma. Cancer Res. 1994;54:2531–2535.

    CAS  PubMed  Google Scholar 

  20. de Zoeten EF, Markovic D, Cohen EP . An optimum anti-melanoma response in mice immunized with fibroblasts transfected with DNA from mouse melanoma cells required the expression of both syngeneic and allogeneic MHC-determinants. Gene Therapy. 2002;9:1163–1172.

    Article  CAS  PubMed  Google Scholar 

  21. Lichtor T, Glick RP, Tarlock K, Moffett S, Mouw E, Cohen EP . Application of interleukin-2 secreting syngeneic/allogeneic fibroblasts in the treatment of primary and metastatic brain tumors. Cancer Gene Ther. 2002;9:464–469.

    Article  CAS  PubMed  Google Scholar 

  22. Lichtor T, Glick RP, Cohen EP . Approaches to the treatment of brain tumors using cytokine-secreting allogeneic fibroblasts. Cancer Therapy. 2003;1:109–120.

    Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from the CINN foundation awarded to Drs Lichtor and Glick, and by NIDCR grant number 1 RO1 DEO13970-O1A2 awarded to Dr Cohen.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Rush University Medical Center, John H Stroger Hospital of Cook County, Chicago, Illinois, USA

    Terry Lichtor, Roberta P Glick & Henry Lin

  2. Hektoen Institute for Medical Research, Chicago, Illinois, USA

    Terry Lichtor, Roberta P Glick & Henry Lin

  3. Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, Illinois, USA

    InSug O-Sullivan & Edward P Cohen

Authors
  1. Terry Lichtor
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roberta P Glick
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Henry Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. InSug O-Sullivan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Edward P Cohen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Terry Lichtor.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lichtor, T., Glick, R., Lin, H. et al. Intratumoral injection of IL-secreting syngeneic/allogeneic fibroblasts transfected with DNA from breast cancer cells prolongs the survival of mice with intracerebral breast cancer. Cancer Gene Ther 12, 708–714 (2005). https://doi.org/10.1038/sj.cgt.7700832

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7700832

Keywords

This article is cited by

Search

Advanced search

Quick links