NON-VIRAL DELIVERY OF INTERLEUKIN-2 AND SOLUBLE FLK-1 INHIBITS METASTATIC AND PRIMARY TUMOR GROWTH IN RENAL CELL CARCINOMA

Abstract

Treatments for renal cell carcinoma, while promising, are still limited by toxicity and cost. In the hopes of finding a novel compound or combination, we developed a plasmid containing the genes for interleukin-2 (IL-2) and soluble vascular endothelial growth factor receptor 2 (msFlk1). The plasmid, p2CMVIL2/msFlk1, demonstrated similar in vitro transgene expression of IL-2 or msFlk1 compared to their single-agent counterparts. Subcutaneous tumor growth was significantly inhibited in the p2CMVIL2/msFlk1 group when delivered locally by the non-viral water soluble polymer, WSLP and exhibited a 50% increase in survival over glucose and single-agent controls. In vivo experimentation demonstrated that WSLP/msFlk1 decreased micro-vessel density in pCMVmsFlk1 and p2CMVIL2/msFlk1 treated groups. Furthermore, tumor-infiltrating lymphocytes expressing CD45RO and CD68 were increased within the tumor microenvironment upon p2CMVIL2/msFlk1 treatment. To determine the effects of p2CMVIL2/msFlk1 in an experimental RENCA lung metastases model, therapeutic DNA was delivered systemically following complexation with the angiogenic endothelial-targeting polymer PEI-g-PEG-RGD. The p2CMVIL2/msFlk1 treatment significantly reduced metastases by 56% over single-agent therapy and increased survival proportions by 50% over all groups. Our work clearly demonstrates that non-viral delivery of p2CMVIL2/msFlk1 can inhibit RENCA growth in a synergistic manner and may represent a new treatment for renal carcinoma.