Genetically modified bone marrow‐derived dendritic cells expressing tumor‐associated viral or “self” antigens induce antitumor immunityin vivo

摘要

AbstractThe 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 E7derived from human papilloma virus (HPV) 16. When applied as a vaccine, these genetically modified DC induced antigen‐specific CD8+cyto‐toxic T lymphocytes (CTL)in vivoand 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 thein vivogrowth 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 i