Lipid-DNA complexes induce potent activation of innate immune responses and antitumor activity when administered intravenously

Cationic lipid-DNA complexes (CLDC) are reported to be safe and effective f or systemic gene delivery, particularly to the lungs. However, we observed that i.v. injection of CLDC induced immunologic effects not previously repo rted. We found that even very low doses of CLDC administered i.v. induced m arked systemic immune activation. This response included strong up regulati on of CD69 expression on multiple cell types and systemic release of high l evels of Th1 cytokines, from both lung and spleen mononuclear cells. CLDC w ere much more potent immune activators on a per weight basis than either LP S or poly(I:C). The remarkable potency of CLDC appeared to result from enha ncement of the immune stimulatory properties of DNA, since cationic lipids alone were without immune stimulatory activity. Systemic treatment with CLD C controlled tumor growth and significantly prolonged survival times in mic e with metastatic pulmonary tumors. NK cells accumulated to high levels in the lungs of CLDC-treated mice, were functionally activated, and released h igh levels of IFN-gamma. The antitumor activity induced by CLDC injection w as dependent on both NK. cells and IFN-gamma, Thus, DNA complexed to cation ic liposomes becomes highly immunostimulatory and capable of inducing stron g antitumor activity when administered systemically.