Phase I study of liposome-DNA complexes encoding the interleukin-2 gene in dogs with osteosarcoma lung metastases.
Systemic gene delivery using cationic liposome-DNA complexes (LDCs) has been shown to elicit potent antitumor activity in mice with tumor metastases to the lungs. However, intravenous gene delivery for treatment of established cancer has not been evaluated previously in a spontaneous, large animal model. We therefore evaluated the safety, toxicity, and efficacy of intravenous gene delivery, using LDCs in dogs with established tumor metastases. Twenty dogs with chemotherapy-resistant osteosarcoma metastases to the lungs received a series of intravenous infusions of cationic liposomes and plasmid DNA encoding the canine interleukin-2 (IL-2) cDNA. Effects of intravenous gene delivery on immune activation, clinical and hematologic parameters, tumor responses, and survival times were assessed. We found that slow intravenous administration of IL-2 LDCs resulted in detectable IL-2 transgene expression in lung tissues of dogs. Repeated intravenous infusions of LDCs were well tolerated by dogs with lung tumor metastases and elicited systemic immune activation, as reflected by fever, leukogram changes, monocyte activation, and increased natural killer cell activity. Three of 20 dogs experienced partial or complete regression of lung metastases after infusion of IL-2 LDCs. Overall survival times were significantly increased in treated dogs compared with historical control animals with the same stage of disease. We conclude that repeated intravenous infusion of LDCs in cancerbearing dogs is safe and well tolerated at low doses and may be capable of eliciting antitumor activity in some animals with advanced tumor metastases.
Dow
Steven
S
Department of Clinical Sciences, Colorado State University, Fort Collins, 80523, USA.
Elmslie
Robyn
R
Kurzman
Ilene
I
MacEwen
Gregory
G
Pericle
Federica
F
Liggitt
Denny
D
D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000628:therapy / Q000662:veterinary; D004247:DNA / Q000008:administration & dosage* / Q000032:analysis; D004283:Dog Diseases / Q000235:genetics / Q000473:pathology / Q000628:therapy; D004285:Dogs; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D018014:Gene Transfer Techniques; D007262:Infusions, Intravenous; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics*; D007694:Killer Cells, Natural; D008081:Liposomes; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary* / Q000628:therapy / Q000662:veterinary; D009362:Neoplasm Metastasis; D012516:Osteosarcoma / Q000235:genetics* / Q000556:secondary* / Q000628:therapy / Q000662:veterinary; D010957:Plasmids; D016019:Survival Analysis; D019076:Transgenes
D007376:Interleukin-2; D008081:Liposomes; D004247:DNA