Therapy of murine mammary carcinoma metastasis with interferon γ and MHC gene-transduced tumour cells

P. Nanni, C. De Giovanni, L. Landuzzi, G. Nicoletti, F. Frabetti, I. Rossi, F. Cavallo, M. Giovarelli, G. Forni, P. L. Lollini

Research output: Contribution to journalArticle

Abstract

Gene-transfected tumour cells were used to cure mice bearing lung metastases by the parental, non-transduced mammary adenocarcinoma (TSA-pc). Repeated subcutaneous (s.c.) administrations of mitomycin C (MitC)-treated interferon γ (IFN-γ) transfectants induced a 90% inhibition in the number of lung metastases. Therapeutic effect required an intact T-cell response, as shown by the lack of efficacy in nude mice. Autocrine stimulation by IFN-γ induces specific modifications in the phenotype of transfectants that acquire a high metastatic ability and show a high expression of IFN-responsive genes; these two features were exploited to design two experimental protocols to obtain an improvement of the therapeutic effect. The increased metastatic ability of IFN-γ transfectants was used to deliver IFN-γ selectively to the lungs of mice bearing TSA-pc pulmonary metastases. A significant therapeutic effect was obtained when TSA-pc experimental metastases were treated by repeated intravenous (i.v.) injections of MitC IFN-γ transfectants. Since i.v. administrations of IFN-γ transfectants did not induce immune memory, the therapeutical effect appeared to depend on the inflammatory-like response activated by local IFN release. To exploit the autocrine stimulation of IFN-sensitive genes an IFN-γ transfectant clone was subjected to a second transfection with an allogeneic class I MHC gene (H-2Kb or H-2D(h)). IFN-γ plus MHC double transfectants maintained IFN-γ release, showed a very high expression of the MHC gene products, stimulated both macrophages and T cells, and were less tumorigenic in immunocompetent mice than the parent IFN-γ clone. Therapeutic efficacy of double transfectant IFN-γ plus H-2Db cells against TSA-pc was superior to single transfectants, showing that the reaction elicited by genetically engineered cells can be selectively tuned to increase therapeutic efficacy.

Original languageEnglish
Pages (from-to)1564-1569
Number of pages6
JournalBritish Journal of Cancer
Volume74
Issue number10
Publication statusPublished - 1996

Keywords

  • Gene therapy
  • Interferon gamma
  • Major histocompatibility complex

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Nanni, P., De Giovanni, C., Landuzzi, L., Nicoletti, G., Frabetti, F., Rossi, I., Cavallo, F., Giovarelli, M., Forni, G., & Lollini, P. L. (1996). Therapy of murine mammary carcinoma metastasis with interferon γ and MHC gene-transduced tumour cells. British Journal of Cancer, 74(10), 1564-1569.