INTERLEUKIN-12 GENE-THERAPY OF MHC-NEGATIVE MURINE MELANOMA METASTASES

Immunological gene therapy of cancer relies heavily on the activation of T cells, but tumors with defects in MHC gene expression are not rec ognized by MHC-restricted T cells, To investigate the potential of cyt okine genes for the therapy of MHC-negative tumors, we transduced B78H 1, a class I-negative murine melanoma clone, with a polycistronic vect or carrying murine interleukin (IL)-12 genes, The clones studied produ ced 400-25,000 pg/ml IL-12; their in vitro growth properties were simi lar to those of parental cells, A complete inhibition of growth was ob served in vivo both after s.c. and i.v. administration of all IL-12 cl ones, IL-12-transduced cells were also used as a therapeutic vaccine i n mice bearing micrometastases by nontransduced parental cells, A sign ificant (80-90%) reduction in the number of lung nodules was obtained, Immunohistochemical analysis and studies in immunocompromised hosts s howed that T cells and natural killer cells had a significant role in the elimination of IL-12-releasing cells, In situ hybridization with c ytokine probes detected a strong increase in the proportion of leukocy tes positive for IFN-gamma, tumor necrosis factor alpha, IL-1 beta, an d IFN-inducible protein 10 at the site of rejection of IL-12-engineere d tumor cells, However, it was clear that the loss of in vivo growth w as also due to T-cell- and natural killer cell-independent factors, po ssibly related to the antiangiogenic properties of IL-12. In conclusio n, tumor therapy based on IL-12 gene transduction was effective on a M HC-negative metastatic tumor, suggesting a possible application to MHC -defective human neoplasms.