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Immunotherapy of Advanced Malignancy by Direct Gene Transfer of an Interleukin-2 DNA/DMRIE/DOPE Lipid Complex: Phase I/II Experience

From the Mayo Clinic and Mayo Foundation, Rochester, MN; Arizona Cancer Center, University of Arizona, Tucson, AZ; University of Colorado Cancer Center, Denver, CO; Scott and White Clinic, Temple, TX; Sidney Kimmel Cancer Agency, and Vical Incorporated, San Diego, and Cedar's Sinai Cancer Center, Los Angeles, CA; and University of Michigan Medical Center, Ann Arbor, MI.

Address reprint requests to Evanthia Galanis, MD, Mayo Clinic, 200 First Street SW, Rochester, MN 55905; email: galanis.evanthia{at}mayo.edu

PURPOSE: We have completed a phase I study, followed by three phase I/II studies, in patients with metastatic melanoma, renal cell carcinoma (RCC), and sarcoma in order to evaluate the safety, toxicity, and antitumor activity of Leuvectin (Vical Inc, San Diego, CA), a gene transfer product containing a plasmid encoding human interleukin (IL)-2 formulated with the cationic lipid 1,2-dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide/dioleyl-phosphatidyl-ethanolamine (DMRIE/DOPE) and administered intratumorally.

PATIENTS AND METHODS: Twenty-four patients were treated in the phase I study. Leuvectin doses were 10 µg, 30 µg, or 300 µg weekly for 6 weeks. In three subsequent phase I/II studies, a total of 52 patients (18 with melanoma, 17 with RCC, and 17 with sarcoma) were treated with further escalating doses of Leuvectin: 300 µg twice a week for 3 weeks, 750 µg weekly for 6 weeks, and 1,500 µg weekly for 6 weeks.

RESULTS: There were no drug-related grade 4 toxicities and only one grade 3 toxicity, but the majority ofpatients experienced mild constitutional symptoms after treatment. In the phase I/II studies, 45 patients were assessable for response (14 with RCC, 16 with melanoma, and 15 with sarcoma). Two patients with RCC and one with melanoma have achieved partial responses lasting from 16 to 19 months and continuing. In addition, two RCC, three melanoma, and six sarcoma patients had stable disease lasting from 3 to 18 months and continuing. The plasmid was detected by polymerase chain reaction assay in the posttreatment samples of 29 of 46 evaluated patients. Immunohistochemistry studies on serial biopsy specimens showed increased IL-2 expression and CD8⁺ infiltration after treatment in the tumor samples of several patients (12 and 16, respectively).

CONCLUSION: Direct intratumoral injection of Leuvectin is a safe and possibly effective immunotherapeutic approach in the treatment of certain tumor types.

November 30, 1998; accepted July 8, 1999.

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