Genetically modified bone marrow-derived dendritic cells expressing tumor-associated viral or "self" antigens induce antitumor immunity in vivo.
The clinical application of synthetic tumor peptide-based vaccines is currently limited to patients with specified major histocompatibility complex (MHC) class I alleles. Such logistic limitations may be overcome using tumor gene-based approaches. Here we describe the effective generation of dendritic cells (DC) expressing tumor peptide-MHC complexes as a result of particle-mediated transfer of genes encoding tumor-associated antigens (TAA). Bone marrow-derived DC were transfected with plasmid DNA encoding the tumor-associated viral antigen E7 derived from human papilloma virus (HPV) 16. When applied as a vaccine, these genetically modified DC induced antigen-specific CD8+ cytotoxic T lymphocytes (CTL) in vivo and promoted the rejection of a subsequent, normally lethal challenge with an HPV 16-transformed tumor cell line. Of greatest interest, immunization of mice with syngeneic DC genetically modified to enhance their presentation of a constitutive "self" epitope derived from the tumor-suppressor gene product p53 caused a significant reduction in the in vivo growth of a chemically induced p53-positive sarcoma. These results suggest that cancer vaccines consisting of DC genetically modified to express TAA of viral or "self" origin effectively induce antitumor immunity in vivo.
Tüting
T
T
Department of Surgery, University of Pittsburgh School of Medicine, PA 15261, USA.
DeLeo
A B
AB
Lotze
M T
MT
Storkus
W J
WJ
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology*; D001854:Bone Marrow Cells / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology; D004274:DNA, Recombinant / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D005260:Female; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D006183:H-2 Antigens / Q000276:immunology; D006801:Humans; D007114:Immunization / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology*; D050725:Papillomavirus E7 Proteins; D012513:Sarcoma, Experimental / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000276:immunology*
D000951:Antigens, Neoplasm; D000956:Antigens, Viral; D019496:Cancer Vaccines; D004274:DNA, Recombinant; D000939:Epitopes; D006183:H-2 Antigens; C024755:H-2K(K) antigen; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D016159:Tumor Suppressor Protein p53; C059731:oncogene protein E7, Human papillomavirus type 16; D007371:Interferon-gamma