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

• Published in: Cancer Vol. 101; no. 11; pp. 2557 - 2566
• Main Authors: Galanis, Evanthia, Burch, Patrick A., Richardson, Ronald L., Lewis, Bradley, Pitot, Henry C., Frytak, Stephen, Spier, Catherine, Akporiaye, Emmanuel T., Peethambaram, Prema P., Kaur, Judith S., Okuno, Scott H., Unni, Krishnan K., Rubin, Joseph
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.12.2004; Wiley-Liss
• Subjects: Adult; Aged; Biological and medical sciences; Cancer Vaccines - administration & dosage; Cancer Vaccines - adverse effects; Cancer Vaccines - immunology; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - immunology; Carcinoma, Renal Cell - therapy; CD8-Positive T-Lymphocytes - immunology; Female; Gene Expression Regulation; gene therapy; Gene Transfer Techniques; Genetic Therapy; Humans; immunotherapy; Interleukin-2 - genetics; Interleukin-2 - immunology; Interleukin-2 - pharmacology; interleukin‐2; Kidney Neoplasms - genetics; Kidney Neoplasms - immunology; Kidney Neoplasms - therapy; Kidneys; Leuvectin; Lipids - administration & dosage; Male; Medical sciences; Middle Aged; Nephrology. Urinary tract diseases; Phosphatidylethanolamines - administration & dosage; Plasmids; Quaternary Ammonium Compounds - administration & dosage; renal cell carcinoma; Survival Analysis; Tumors; Tumors of the urinary system; Kidney disease; Human; interleukin-2; Urinary system disease; Carcinoma; Cytokine; Intratumoral administration; Malignant tumor; Metastasis; renal cell carcinoma; Cancerology; Treatment; Gene; Interleukin 2; Formulation; Immunotherapy; Genetics; Grawitz tumor; Advanced stage; Leuvectin; Gene therapy
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.20653

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. Cancer 2004. © 2004 American Cancer Society. The authors investigated the safety and efficacy of in situ vaccination with a cationic lipid formulation of the human interleukin‐2 (IL‐2) gene in 31 patients with metastatic renal cell carcinoma. Treatment was well tolerated and resulted in three objective responses (two partial and one complete), lasting from 32 months to 6 years, and seven cases of disease stabilization. Laboratory analysis of tumor samples revealed that posttreatment, IL‐2 plasmid DNA was present in six of eight patients, IL‐2 expression in tumor cells was increased in four of eight patients, and tumor infiltration by CD8‐positive lymphocytes was increased in five of eight patients.