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Interleukin 12 Gene Therapy of MHC-negative Murine Melanoma Metastases¹

Institute for Cancer Research, University of Bologna, I-40126 Bologna [P. N., I. R., C. D. G., P-L. L.]; National Cancer Institute of Genoa, Biotechnology Satellite Unit of Bologna, I-40126 Bologna [L. L., G. N.]; Department of Experimental Medicine, University of Rome, I-00161 Rome [A. S.]; and Experimental Oncology D. National Cancer Institute, I-20133 Milan [M. P., M. P. C.]; Italy

Immunological gene therapy of cancer relies heavily on the activation of T cells, but tumors with defects in MHC gene expression are not recognized by MHC-restricted T cells. To investigate the potential of cytokine genes for the therapy of MHC-negative tumors, we transduced B78H1, a class I-negative murine melanoma clone, with a polycistronic vector carrying murine interleukin (IL)-12 genes. The clones studied produced 400–25,000 pg/ml IL-12; their in vitro growth properties were similar to those of parental cells. A complete inhibition of growth was observed in vivo both after s.c. and i.v. administration of all IL-12 clones. IL-12-transduced cells were also used as a therapeutic vaccine in mice bearing micrometastases by nontransduced parental cells. A significant (80–90%) reduction in the number of lung nodules was obtained. Immunohistochemical analysis and studies in immunocompromised hosts showed that T cells and natural killer cells had a significant role in the elimination of IL-12-releasing cells. In situ hybridization with cytokine probes detected a strong increase in the proportion of leukocytes positive for IFN-, tumor necrosis factor , IL-1ß, and IFN-inducible protein 10 at the site of rejection of IL-12-engineered tumor cells. However, it was clear that the loss of in vivo growth was also due to T-cell- and natural killer cell-independent factors, possibly related to the antiangiogenic properties of IL-12. In conclusion, tumor therapy based on IL-12 gene transduction was effective on a MHC-negative metastatic tumor, suggesting a possible application to MHC-defective human neoplasms.

¹ Supported by grants from the Italian Association for Cancer Research, the Italian Ministry for University and Research, and the National Research Council. I. R. is the recipient of an Italian Association for Cancer Research fellowship.

² To whom requests for reprints should be addressed, at Istituto di Cancerologia, Viale Filopanti 22, I-40126 Bologna, Italy. Fax: 39-51-242-169; E-mail: nanni@cancer.unibo.it.

Received 10/15/97. Accepted 1/16/98.

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