Phase I study of liposome-DNA complexes encoding the interleukin-2 gene in dogs with osteosarcoma lung metastases
Steven Dow1, Robyn Elmslie, Ilene Kurzman
1Department of Clinical Sciences, Colorado State University, Fort Collins, 80523, USA.
Abstract:
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.
Insights
Systemic gene delivery using cationic liposome-DNA complexes (LDCs) showed safety and efficacy in dogs with lung metastases. This approach activated the immune system and improved survival in osteosarcoma patients.
Area of Science:
- Oncology
- Gene Therapy
- Immunology
Background:
- Systemic gene delivery with cationic liposome-DNA complexes (LDCs) shows promise for lung metastases treatment.
- Previous studies focused on mouse models, lacking large animal data for established cancers.
Purpose of the Study:
- Evaluate safety, toxicity, and efficacy of intravenous gene delivery using LDCs in dogs with established lung metastases.
- Assess immune activation, clinical parameters, tumor response, and survival.
Main Methods:
- Twenty dogs with chemotherapy-resistant osteosarcoma lung metastases received intravenous infusions of IL-2 LDCs.
- Monitored IL-2 transgene expression, immune responses, clinical signs, and survival.
Main Results:
- Slow intravenous IL-2 LDC administration led to detectable IL-2 transgene expression in lung tissues.
- Repeated LDC infusions were well-tolerated, inducing systemic immune activation (fever, leukogram changes, increased NK cell activity).
- Three dogs showed partial or complete regression of lung metastases; survival times increased compared to historical controls.
Conclusions:
- Repeated intravenous LDC infusions are safe and well-tolerated in cancer-bearing dogs at low doses.
- This gene delivery method may elicit antitumor activity in advanced metastatic disease.
- Intravenous gene therapy shows potential for treating spontaneous large animal cancers.
