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
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.