TREATMENT OF ESTABLISHED TUMORS WITH A NOVEL VACCINE THAT ENHANCES MAJOR HISTOCOMPATIBILITY CLASS-II PRESENTATION OF TUMOR-ANTIGEN

Presentation of antigenic peptides by MHC class II molecules to CD4(+) T cells is critical to the generation of antitumor immunity. In an at tempt to enhance MHC class II antigen processing, we linked the sortin g signals of the lysosome-associated membrane protein (LAMP-1) to the cytoplasmic/nuclear human papilloma virus (HPV-16) E7 antigen, creatin g a chimera (Sig/E7/LAMP-1). Previously, we found that expression of t his chimera in vitro and in vivo with a recombinant vaccinia vector ta rgeted E7 to endosomal and lysosomal compartments and enhanced MHC cla ss II presentation to CD4(+) T cells compared to vaccinia expressing w ild-type E7. In the current study, we tested these recombinant vaccini a for in vivo protection against an E7(+) tumor, TC-1, which was deriv ed from primary epithelial cells of C57BL/6 mice cotransformed with HP V-16 E6 and E7 and c-Ha-ras oncogenes. All mice vaccinated with 1 x 10 (7) plaque-forming units of wild-type E7-vaccinia showed progressive t umor growth when challenged with a tumorigenic dose of TC-1 tumor cell s; in contrast, 80% of mice vaccinated with the chimeric Sig/E7/LAMP1 vaccinia remained tumor free 3 months after tumor injection. Furthermo re, treatment with the Sig/E7/LAMP-1 vaccinia vaccine cured mice with small established TC-1 tumors, whereas the wild-type E7-vaccinia showe d no effect on this established tumor burden. These findings point out the therapeutic limitations of recombinant vaccinia expressing unmodi fied tumor antigens. Further, they demonstrate that modifications that reroute a cytosolic tumor antigen to the endosomal/lysosomal compartm ent can profoundly improve the in vivo therapeutic potency of recombin ant vaccines.