Intratumoral interleukin 2 for renal-cell carcinoma by direct gene transfer of a plasmid DNA/DMRIE/DOPE lipid complex

Citation
Dmj. Hoffman et Ra. Figlin, Intratumoral interleukin 2 for renal-cell carcinoma by direct gene transfer of a plasmid DNA/DMRIE/DOPE lipid complex, WORLD J URO, 18(2), 2000, pp. 152-156
Citations number
43
Categorie Soggetti
Urology & Nephrology
Journal title
WORLD JOURNAL OF UROLOGY
ISSN journal
07244983 → ACNP
Volume
18
Issue
2
Year of publication
2000
Pages
152 - 156
Database
ISI
SICI code
0724-4983(200004)18:2<152:II2FRC>2.0.ZU;2-E
Abstract
Metastatic renal-cell carcinoma (RCC) is not responsive to conventional cyt otoxic chemotherapy, but a subset of patients achieve a durable remission w ith the use of interleukin-2 (IL-2). IL-2 is currently the only Food and Dr ug Administration (FDA)-approved treatment for metastatic RCC, and it benef its 10-20% of those who receive it. However, it is accompanied by significa nt, occasionally life-threatening toxicity. Attempts to maintain the effica cy of IL-2 while minimizing systemic side effects have led to the developme nt of IL-2 gene therapies. Leuvectin is a plasmid DNA/lipid com Flex compos ed of a plasmid DNA expression vector (VCL-1102, 30) encoding human IL-2 co mplexed 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 I L-2 plasmid DNA/DMRIE/DOPE complex results in the expression of sustained l evels of biologically active IL-2. Established human tumor cell lines and p rimary 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 prim ary tumor cells. In preclinical efficacy studies in a murine model of renal -cell carcinoma the direct intratumoral administration of an IL-2 plasmid D NA/DMRIE/ DOPE complex resulted in complete tumor regression in the majorit y of mice. In preclinical animal-safety studies, repeated administration of Leuvectin was safe and well tolerated. Following these promising preclinic al trials, Leuvectin has been taken into clinical trial. The results of two early studies indicate that Leuvectin is safe, is free of systemic toxicit y, and has biologic activity.