Induction of antitumor immunity with dendritic cells transduced with adenovirus vector-encoding endogenous tumor-associated antigens.
Dendritic cells (DCs) are professional Ag-presenting cells that are being considered as potential immunotherapeutic agents to promote host immune responses against tumor Ags. In this study, recombinant adenovirus (Ad) vectors encoding melanoma-associated Ags were used to transduce murine DCs, which were then tested for their ability to activate CTL and induce protective immunity against B16 melanoma tumor cells. Immunization of C57BL/6 mice with DCs transduced with Ad vector encoding the hugp100 melanoma Ag (Ad2/hugp100) elicited the development of gp100-specific CTLs capable of lysing syngeneic fibroblasts transduced with Ad2/hugp100, as well as B16 cells expressing endogenous murine gp100. The induction of gp100-specific CTLs was associated with long term protection against lethal s.c. challenge with B16 cells. It was also possible to induce effective immunity against a murine melanoma self Ag, tyrosinase-related protein-2, using DCs transduced with Ad vector encoding the Ag. The level of antitumor protection achieved was dependent on the dose of DCs and required CD4+ T cell activity. Importantly, immunization with Ad vector-transduced DCs was not impaired in mice that had been preimmunized against Ad to mimic the immune status of the general human population. Finally, DC-based immunization also afforded partial protection against established B16 tumor cells, and the inhibition of tumor growth was improved by simultaneous immunization against two melanoma-associated Ags as opposed to either one alone. Taken together, these results support the concept of cancer immunotherapy using DCs transduced with Ad vectors encoding tumor-associated Ags.
Genzyme Corporation, Genzyme Molecular Oncology, Framingham, MA 01701, USA. jkaplan@genzyme.com
J M
JM
Kaplan
Q
Q
Yu
S T
ST
Piraino
S E
SE
Pennington
S
S
Shankara
L A
LA
Woodworth
B L
BL
Roberts
D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D001854:Bone Marrow Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation* / Q000821:virology; D005260:Female; D005822:Genetic Vectors / Q000276:immunology; D006801:Humans; D016233:Immunotherapy, Active; D016219:Immunotherapy, Adoptive / Q000379:methods; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy*; D058950:Melanoma-Specific Antigens; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection / Q000276:immunology*; D058951:gp100 Melanoma Antigen
D000951:Antigens, Neoplasm; D058950:Melanoma-Specific Antigens; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C548637:PMEL protein, human; C548642:Pmel protein, mouse; D058951:gp100 Melanoma Antigen