title: Antitumor activity of cationic lipid complexed with immunostimulatory DNA.
abstract: We previously reported that treatment of intraperitoneal tumors with complexes of cationic lipid and noncoding plasmid DNA leads to the development of a specific, cytotoxic T-cell response correlating with the rejection of established tumor cells as well as subsequent tumor re-challenge. Here, focusing on an intraperitoneal AB12 mesothelioma model, we show that the anticancer effects of the lipid:DNA complex are associated with DNA containing immunostimulatory CpG motifs. Complexes prepared with cationic lipid and bacterial plasmid DNA, Escherichia coli genomic DNA fragments, or synthetic immunostimulatory CpG oligodeoxynucleotides provided a substantial survival benefit, whereas eukaryotic DNA and methylated bacterial DNA had little or no therapeutic activity. Alternative inflammatory stimuli such as thioglycolate, poly(I:C), and incomplete or complete Freund's adjuvant failed to reproduce the antitumor activity obtained with the lipid:DNA complex. The innate immune response triggered by lipid:DNA complexes led to the development of a systemic immune response against tumor cells that allowed animals to reject tumors not only at the intraperitoneal treatment site, but also at a distal subcutaneous site. These data demonstrate that immunostimulatory DNA complexed with cationic lipid is a potent inducer of innate and adaptive immune responses against tumor cells and represents a potentially useful tool in the immunotherapy of cancers for which tumor-associated antigens have not been identified.
authors.affiliation: Genzyme Corporation, Framingham, Massachusetts 01701, USA.
authors.forename: S
authors.initials: S
authors.lastname: Rudginsky
authors.forename: W
authors.initials: W
authors.lastname: Siders
authors.forename: L
authors.initials: L
authors.lastname: Ingram
authors.forename: J
authors.initials: J
authors.lastname: Marshall
authors.forename: R
authors.initials: R
authors.lastname: Scheule
authors.forename: J
authors.initials: J
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D018899:CpG Islands / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D019175:DNA Methylation; D004269:DNA, Bacterial / Q000276:immunology* / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005620:Freund's Adjuvant / Q000276:immunology / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology; D007249:Inflammation / Q000139:chemically induced; D007274:Injections, Intraperitoneal; D008055:Lipids / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology*; D008545:Melanoma / Q000235:genetics / Q000628:therapy; D008654:Mesothelioma / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D051379:Mice; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000235:genetics / Q000628:therapy; D051381:Rats; D016019:Survival Analysis; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D004269:DNA, Bacterial; D004337:Drug Carriers; D008055:Lipids; D005620:Freund's Adjuvant