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

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 gamma (IFN-gamma) 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-gamma 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-gamma transfectants was used to deliver IFN-gamma 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-gamma transfectants. Since i.v. administrations of IFN-gamma 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-gamma transfectant clone was subjected to a second transfection with an allogeneic class I MHC gene (H-2K(b) or H-2D(h)). IFN-gamma plus MHC double transfectants maintained IFN-gamma 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-gamma clone. Therapeutic efficacy of double transfectant IFN-gamma plus H-2D(b) 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.