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 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 10(7) 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.
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287-6417, USA.
K Y
KY
Lin
F G
FG
Guarnieri
K F
KF
Staveley-O'Carroll
H I
HI
Levitsky
J T
JT
August
D M
DM
Pardoll
T C
TC
Wu
D000818:Animals; D017951:Antigen Presentation; D000957:Antigens, Viral, Tumor / Q000276:immunology*; D001483:Base Sequence; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D014614:Vaccines, Synthetic / Q000276:immunology / Q000627:therapeutic use
D000957:Antigens, Viral, Tumor; D000949:Histocompatibility Antigens Class II; D014614:Vaccines, Synthetic