Antitumor activity of cationic lipid complexed with immunostimulatory DNA.
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.
Rudginsky
S
S
Genzyme Corporation, Framingham, Massachusetts 01701, USA.
Siders
W
W
Ingram
L
L
Marshall
J
J
Scheule
R
R
Kaplan
J
J
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
D000970:Antineoplastic Agents; D016207:Cytokines; D004269:DNA, Bacterial; D004337:Drug Carriers; D008055:Lipids; D005620:Freund's Adjuvant