Intratumoral administration of a 1,2-dimyristyloxypropyl-3- dimethylhydroxyethyl ammonium bromide/dioleoylphosphatidylethanolamine formulation of the human interleukin-2 gene in the treatment of metastatic renal cell carcinoma

BACKGROUND. Leuvectin (Vical Inc., San Diego, CA) is a gene transfer product in which a plasmid encoding the human interleukin-2 (IL-2) gene is complexed with the cationic lipid 1,2-dimyristyloxypropyl-3-dimethylhydroxyethyl ammonium bromide/dioleoylphosphatidylethanolamine (DMRIE/DOPE). In the current study, the authors investigated the safety and efficacy of in situ vaccination with Leuvectin in patients with metastatic renal cell carcinoma. METHODS. Thirty-one patients with metastatic renal cell carcinoma were treated with intratumorally administered Leuvectin at doses ranging from 0.75 to 4 mg. These patients subsequently were evaluated for response and for treatment-related toxicity. RESULTS. Treatment was well tolerated: no Grade 3 or 4 toxicities were observed in association with the study agent. Documented side effects included Grade 1 pain at the injection site (20%); mild (i.e., Grade 1 or 2) constitutional symptoms, including malaise/myalgia, low-grade fever, and chills (74%); Grade 1 fatigue (19%); Grade 1 or 2 nausea (10%); and Grade 2 allergy (1 occurrence). Two patients experienced partial responses, which endured for 32 months and 6 years, respectively, and 1 patient currently is experiencing a pathologic complete response, which, to date, has persisted for 50 months; thus, the overall response rate was 10%. In addition, 7 patients (23%) experienced disease stabilization for a median of 8 months (range, 4-48 months). The median duration of survival from the start of Leuvectin treatment was 11 months (range, 2-72 months), with a 1-year survival rate of 48% and a 3-year survival rate of 19%. Laboratory analysis of tumor samples revealed the presence of IL-2 plasmid DNA in six of eight patients posttreatment, increased IL-2 expression in tumor cells in four of eight patients posttreatment, and increased tumor infiltration by CD8-positive lymphocytes in five of eight patients posttreatment. CONCLUSIONS. Immunotherapy with intratumorally administered Leuvectin is safe and can lead to durable objective responses in patients with metastatic renal cell carcinoma.