Published in Cancer Detection and Prevention 1998; 22(Supplement 1).

Murine mammary carcinoma: Control and treatment of primary and metastatic tumors

S. Baskar, PhD

Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD, 21250. U.S.A.

AIM: This study investigates the use of gene-modified tumor cells as cellular vaccine to control and treat the primary and metastatic tumors. METHODS: Balb/c-derived mammary tumor cell lines (410.4 and 66.1) were transfected to constitutively express syngenic major histocompatibility complex class II proteins (I-Ad), the costimulatory molecules B7.1, B7.2 or co-express I-Ad and B7.1 molecules. Stable transfectants expressing these molecules were used as cellular vaccine to induce anti-tumor immunity. RESULTS: The wild type 410.4 and 66.1 tumor cells as well as control transfectants grew progressively in syngenic Balb/c and Balb/c nude mice. By contrast, transfectants expressing either I-Ad or B7 molecules alone showed a significant delay in their in vivo growth in Balb/c mice, and in some mice reduced growth or total rejection was seen. Multiple injections of irradiated transfectants, not wild type tumor cells, induced protective immunity against subsequent challenge with live wild type tumor cells. Administration of low dose interleukin 12 (IL-12) reduced the growth of wild type tumor cells, and completely abrogated the growth of B7.1 transfectants. Metastasis from a preestablished wild type tumor was highly reduced (in some cases prevented) by therapeutic treatment with a combination of irradiated transfectants and IL-12. Transfectants co-expressing I-Ad and B7.1 molecules were mostly rejected, and also failed to metastasize into lungs. There was no difference in the pattern of growth/ rejection of the tumor cells in the IL-4 knock out Balb/c mice as compared to the normal Balb/c mice. CONCLUSIONS: The gene-modified tumor cells used are able to activate specific CD4+ and CD8+ T cells and induce tumor immunity. IL-12 helps to generate a vigorous anti-tumor immunity that can significantly reduce metastasis. Therapeutic treatment with a combination of immunogenic transfectants and IL-12 was successful in causing regression of preestablished tumor and abrogation of metastasis.

KEY WORDS: mammary tumor, MHC class II, B7 Costimulation, B7 Costimulation, Interleukin 12, Metastasis, .

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Paper presented at the International Symposium on the Impact of Biotechnology on Prediction, Prevention and Treatment of Cancer; Nice, France; October 24 - 27, 1998; in the section on Immunotherapy.