Presentation of antigenic peptides by MHC class II molecules to CD4@ T cells is critical to the generation of antitumor immunity. In an attempt to enhance MHC class II antigen processing, we linked the sorting signals of the lysosome-associated membrane protein (LAMP-i) to the cytoplas mic/nuclear human papilloma virus (HPV-i6) E7 antigen, creating a chimera (SigIE7ILAMP.i). Previously, we found that expression of this chimera in vitro and in vivo with a recombinant vaccinia vector targeted E7 to endosomal and lysosomal compartments and enhanced MHC class II presentation to CD4@T cells compared to vaccinia expressing wild-type E7. In the current study, we tested these recombinant vaccinia for in vivo protection against an E7@tumor, TC-1, which was derived from primary epithelial cells of C57BL/6 mice cotransformed with HPV.i6 E6 and E7 and c-Ha.ras oncogenes. All mice vaccinated with i X i07 plaque-forming units of wild-type E7-vaccinia showed progressive tumor growth when challenged with a tumongenic dose of TC-i tumor cells; in contrast, 80% of mice vaccinated with the chimeric SigIE7ILAMP1vaccinia remained tumor free 3 months after tumor injection. Furthermore, treatment with the SigIE7ILAMP.i vaccinia vaccine cured mice with small established TC-i tumors, whereas the wild-type E7-vaccinia showed no effect on this established tumor burden. These findings point out the therapeutic limi tations of recombinant vaccinia expressing unmodified tumor antigens. Further, they demonstrate that modifications that reroute a cytosolic tumor antigen to the endosomal/lysosomal compartment can profoundly improve the in vivo therapeutic potency of recombinant vaccines.
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