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Departments of Pathology [K-Y. L., T-C. W.], Pharmacology and Molecular Science [F. G. G., J. T. A.], Surgery [K. F. S-O.], and Oncology [H. I. L., J. T. A., D. M. P.], The Johns Hopkins Medical Institutions, Baltimore, Maryland 21287-6417
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-1) to the cytoplasmic/nuclear human papilloma virus (HPV-16) E7 antigen, creating a chimera (Sig/E7/LAMP-1). 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-16 E6 and E7 and c-Ha-ras oncogenes. All mice vaccinated with 1 x 107 plaque-forming units of wild-type E7-vaccinia showed progressive tumor growth when challenged with a tumorigenic dose of TC-1 tumor cells; in contrast, 80% of mice vaccinated with the chimeric Sig/E7/LAMP1 vaccinia remained tumor free 3 months after tumor injection. Furthermore, treatment with the Sig/E7/LAMP-1 vaccinia vaccine cured mice with small established TC-1 tumors, whereas the wild-type E7-vaccinia showed no effect on this established tumor burden. These findings point out the therapeutic limitations 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.
1 This work was supported by NIH Grants 5 PO1 34582-01 and P50 CA62924, and by a gift from Mr. and Mrs. Zandy Leaderman. F. G. G. was supported by the Gustavus and Louise Pfeiffer Research Foundation.
2 To whom requests for reprints should be addressed, at Department of Pathology, The Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287. Phone: (410) 614-3899; Fax: (410) 614-3548.
Received 10/27/95. Accepted 11/22/95.
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