Intratumoral interleukin 2 for renal-cell carcinoma by direct gene transfer of a plasmid DNA/DMRIE/DOPE lipid complex.
Metastatic renal-cell carcinoma (RCC) is not responsive to conventional cytotoxic chemotherapy, but a subset of patients achieve a durable remission with the use of interleukin-2 (IL-2). IL-2 is currently the only Food and Drug Administration (FDA)-approved treatment for metastatic RCC, and it benefits 10-20% of those who receive it. However, it is accompanied by significant, occasionally life-threatening toxicity. Attempts to maintain the efficacy of IL-2 while minimizing systemic side effects have led to the development of IL-2 gene therapies. Leuvectin is a plasmid DNA/lipid complex composed of a plasmid DNA expression vector (VCL-1102, 30) encoding human IL-2 complexed in a 5:1 mass ratio with DMRIE/DOPE lipid (1,2-dimyristyloxypropyl-3-dimethylhydroxyethyl ammonium bromide/dioleoylphosphatidyl ethanolamine), which has been developed for the treatment of malignancy. DMRIE/DOPE is a cationic lipid that has been shown to facilitate in vitro transfection of plasmid DNA. It has been demonstrated that in vitro transfection with the IL-2 plasmid DNA/DMRIE/DOPE complex results in the expression of sustained levels of biologically active IL-2. Established human tumor cell lines and primary human tumor cells obtained from biopsies are readily transfected in vitro, resulting in the expression of IL-2. Following in vitro transfection, IL-2 expression has been found to persist for up to several weeks in primary tumor cells. In preclinical efficacy studies in a murine model of renal-cell carcinoma the direct intratumoral administration of an IL-2 plasmid DNA/DMRIE/DOPE complex resulted in complete tumor regression in the majority of mice. In preclinical animal-safety studies, repeated administration of Leuvectin was safe and well tolerated. Following these promising preclinical trials, Leuvectin has been taken into clinical trial. The results of two early studies indicate that Leuvectin is safe, is free of systemic toxicity, and has biologic activity.
Hoffman
D M
DM
Department of Medicine, University of California, Los Angeles, School of Medicine, 90095, USA.
Figlin
R A
RA
D000368:Aged; D001706:Biopsy; D002292:Carcinoma, Renal Cell / Q000556:secondary* / Q000628:therapy*; D018014:Gene Transfer Techniques; D006801:Humans; D007167:Immunotherapy; D007376:Interleukin-2 / Q000009:adverse effects / Q000235:genetics* / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000473:pathology; D008055:Lipids / Q000493:pharmacokinetics; D008113:Liver Neoplasms / Q000556:secondary* / Q000628:therapy*; D008175:Lung Neoplasms / Q000556:secondary / Q000628:therapy; D008297:Male; D010957:Plasmids; D000644:Quaternary Ammonium Compounds / Q000493:pharmacokinetics; D011994:Recombinant Proteins / Q000235:genetics / Q000627:therapeutic use; D019076:Transgenes
D007376:Interleukin-2; D008055:Lipids; D000644:Quaternary Ammonium Compounds; D011994:Recombinant Proteins; C087276:(3-dimyristyloxypropyl)(dimethyl)(hydroxyethyl)ammonium