title: Immunotherapy of advanced malignancy by direct gene transfer of an interleukin-2 DNA/DMRIE/DOPE lipid complex: phase I/II experience.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Twenty-four patients were treated in the phase I study. Leuvectin doses were 10 microg, 30 microg, or 300 microg 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 microg twice a week for 3 weeks, 750 microg weekly for 6 weeks, and 1,500 microg weekly for 6 weeks.
  
  
  RESULTS
  There were no drug-related grade 4 toxicities and only one grade 3 toxicity, but the majority of patients 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).
  
  
  CONCLUSIONS
  Direct intratumoral injection of Leuvectin is a safe and possibly effective immunotherapeutic approach in the treatment of certain tumor types.
authors.affiliation: Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA. galanis.evanthia@mayo.edu
authors.forename: E
authors.initials: E
authors.lastname: Galanis
authors.forename: E M
authors.initials: EM
authors.lastname: Hersh
authors.forename: A T
authors.initials: AT
authors.lastname: Stopeck
authors.forename: R
authors.initials: R
authors.lastname: Gonzalez
authors.forename: P
authors.initials: P
authors.lastname: Burch
authors.forename: C
authors.initials: C
authors.lastname: Spier
authors.forename: E T
authors.initials: ET
authors.lastname: Akporiaye
authors.forename: J J
authors.initials: JJ
authors.lastname: Rinehart
authors.forename: J
authors.initials: J
authors.lastname: Edmonson
authors.forename: R E
authors.initials: RE
authors.lastname: Sobol
authors.forename: C
authors.initials: C
authors.lastname: Forscher
authors.forename: V K
authors.initials: VK
authors.lastname: Sondak
authors.forename: B D
authors.initials: BD
authors.lastname: Lewis
authors.forename: E C
authors.initials: EC
authors.lastname: Unger
authors.forename: M
authors.initials: M
authors.lastname: O'Driscoll
authors.forename: L
authors.initials: L
authors.lastname: Selk
authors.forename: J
authors.initials: J
authors.lastname: Rubin
mesh_terms: D000328:Adult; D000368:Aged; D016827:CD8 Antigens / Q000032:analysis; D002292:Carcinoma, Renal Cell / Q000473:pathology / Q000628:therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D007150:Immunohistochemistry; D007376:Interleukin-2 / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000473:pathology / Q000628:therapy*; D008055:Lipids / Q000235:genetics / Q000627:therapeutic use; D008297:Male; D008545:Melanoma / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D010957:Plasmids / Q000235:genetics; D016133:Polymerase Chain Reaction; D000644:Quaternary Ammonium Compounds / Q000627:therapeutic use; D012509:Sarcoma / Q000473:pathology / Q000628:therapy*; D012878:Skin Neoplasms / Q000473:pathology / Q000628:therapy*
chemical_list: D016827:CD8 Antigens; D007376:Interleukin-2; D008055:Lipids; D000644:Quaternary Ammonium Compounds; C087276:(3-dimyristyloxypropyl)(dimethyl)(hydroxyethyl)ammonium