Effectiveness of combined interleukin 2 and B7.1 vaccination strategy is dependent on the sequence and order: a liposome-mediated gene therapy treatment for bladder cancer.
We have developed a novel liposome-mediated immunogene therapy using interleukin 2 (IL-2) and B7.1 in a murine bladder cancer model. A carcinogen-induced murine bladder cancer cell line, MBT-2, was transfected with cationic liposome 1,2-dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide/dioleolylphosphatidylethanolamine and IL-2 plasmid. The optimized transfection condition generated IL-2 levels of 245-305 ng/10(6) cells/24 h, 100-fold higher than the levels seen with retrovirus transfection. Ninety percent of the peak level of IL-2 production was maintained for up to 11 days after transfection. Animal studies were conducted in C3H/HeJ female mice with 2 x 10(4) MBT-2 cells implanted orthotopically on day 0. Multiple vaccination schedules were performed with i.p. injection of 5 x 10(6) IL-2 and/or B7.1 gene-modified cell preparations. The greatest impact on survival was observed with the day 5, 10, and 15 regimen. Control animals receiving retrovirally gene-modified MBT-2/IL-2 cell preparations had a median survival of 29 days. Animals receiving the IL-2 liposomally gene-modified cell preparation alone had a median survival of 46 days. Seventy-five percent of animals receiving IL-2 followed by B7.1 gene-modified tumor vaccines were the only group to show complete tumor-free survival at day 60. All of these surviving animals rejected the parental MBT-2 tumor rechallenge and survived at day 120 with a high CTL response. In conclusion, liposome-mediated transfection demonstrates a clear advantage as compared with the retroviral system in the MBT-2 model. Multi-agent as opposed to single-agent cytokine gene-modified tumor vaccines were beneficial. These "targeted" sequential vaccinations using IL-2 followed by B7.1 gene-modified tumor cells significantly increased a systemic immune response that translated into increased survival.
Department of Urology, The Cleveland Clinic Foundation, Ohio 44195, USA. LARCHIW@ccf.org
W A
WA
Larchian
Y
Y
Horiguchi
S K
SK
Nair
W R
WR
Fair
W D
WD
Heston
E
E
Gilboa
D000818:Animals; D018122:B7-1 Antigen / Q000627:therapeutic use*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D004337:Drug Carriers; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D020404:Glycerophospholipids; D007376:Interleukin-2 / Q000235:genetics* / Q000627:therapeutic use; D008055:Lipids; D008081:Liposomes; D051379:Mice; D008809:Mice, Inbred C3H; D010714:Phosphatidylethanolamines; D000644:Quaternary Ammonium Compounds; D011994:Recombinant Proteins / Q000235:genetics / Q000627:therapeutic use; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection / Q000379:methods; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000276:immunology / Q000628:therapy*
C410262:1,2-dioleoyl-glycero-3-phosphatidyl ethanolamine; D018122:B7-1 Antigen; D019496:Cancer Vaccines; D004337:Drug Carriers; D020404:Glycerophospholipids; D007376:Interleukin-2; D008055:Lipids; D008081:Liposomes; D010714:Phosphatidylethanolamines; D000644:Quaternary Ammonium Compounds; D011994:Recombinant Proteins; C087276:(3-dimyristyloxypropyl)(dimethyl)(hydroxyethyl)ammonium