Use of interleukin-12 plasmid nanocomplexes as a general treatment strategy against disseminated peritoneal malignancies.

3304 The strong anti-cancer properties of interleukin-12 (IL-12) make it a sought-after target for therapeutic development. The effects of IL-12 are mediated through induction of local and systemic immune responses and strong anti-angiogenic characteristics. Specifically, IL-12 administration is associated with T-lymphocyte and natural killer (NK) cell proliferation, activation of cytotoxic T-lymphocytes and secretion of interferon-gamma (IFN-γ). The anti-angiogenic effects result from IFN-γ induced stimulation of monokine induced by IFN-γ (MIG) and IFN- inducible protein (IP-10) and direct inhibitory effects of VEGF mRNA. We have developed a non-viral polymeric delivery system (PPC) formulated with a plasmid encoding for IL-12 that when delivered intraperitoneally is an effective inhibitor of experimentally induced ovarian cancer in mice. Efficacy is enhanced by combining treatment with standard chemotherapeutic agents such as Taxol® and Paraplatin®. Currently this product is being evaluated clinically in patients with recurrent ovarian cancer. We were interested examining use of this therapy against other forms of cancer known to disseminate into the peritoneal cavity. For these studies a murine IL-12 plasmid was formulated with the polymeric delivery system PPC which is composed of a low molecular weight branched polyethylenimine covalently linked with functional groups of polyethyleneglycol and cholesterol. When formulated at 11:1 nitrogen to phosphate ratio the DNA is fully condensed into nanoparticles of ~100 nm diameter. Peritoneally disseminated tumor models of pancreatic cancer (PAN-02) and colorectal cancer (CT-26) were established in syngeneic mice. At various times after tumor implant, mice were treated with mIL-12/PPC or a combination of mIL-12/PPC and standard chemotherapy. In mice with pancreatic tumors, mIL-12/PPC treatment resulted in dose dependent increases in median survival times of up to 127% over untreated controls. In the highest dose treatment group 42.9% achieved long-term survival of over 100 days compared to 0% in the untreated control groups. When mIL-12/PPC treatment was combined with Gemzar® treatment survival was significantly improved over either monotherapy. In mice with colorectal tumors a 35% increase in median survival was seen in response to mIL-12/PPC therapy and improved long-term survival to 40% compared to 0% for the untreated controls. Long-term survival was increased to 67% by combining mIL-12/PPC administration with 5-fluorouracil (5-FU). The results of these studies indicate that IL-12 plasmid formulated with a polymeric delivery system is useful in treating both pancreatic and colorectal disseminated cancer. Further, mIL-12/PPC administration is compatible with standard chemotherapeutics producing added efficacy benefits and suggests broad applicability for treating a wide variety of malignancies.