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

• Published in: Clinical cancer research Vol. 6; no. 7; pp. 2913 - 2920
• Main Authors: LARCHIAN, W. A, HORIGUCHI, Y, NAIR, S. K, FAIR, W. R, HESTON, W. D. W, GILBOA, E
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.07.2000
• Subjects: Animals; Antineoplastic agents; B7-1 Antigen - therapeutic use; Biological and medical sciences; Cancer Vaccines - therapeutic use; Combined Modality Therapy; Disease-Free Survival; Drug Administration Schedule; Drug Carriers; Female; Genetic Therapy - methods; Glycerophospholipids; Immunotherapy; Interleukin-2 - genetics; Interleukin-2 - therapeutic use; Lipids; Liposomes; Medical sciences; Mice; Mice, Inbred C3H; Pharmacology. Drug treatments; Phosphatidylethanolamines; Quaternary Ammonium Compounds; Recombinant Proteins - genetics; Recombinant Proteins - therapeutic use; T-Lymphocytes, Cytotoxic - immunology; Transfection - methods; Tumor Cells, Cultured; Urinary Bladder Neoplasms - immunology; Urinary Bladder Neoplasms - therapy; Antineoplastic agent; Animal model; Vaccination; Stimulation; Drug carrier; Transfection; Interleukin 2; Urinary bladder; Sequential method; Immunotherapy; Established cell line; Drug combination; Urinary system disease; Immune response; Treatment efficiency; Rodentia; Liposome; Vaccine; Urinary tract disease; Malignant tumor; Gene expression; Vertebrata; Mammalia; Treatment; Mouse; Animal; Bladder disease; Gene therapy
• ISSN: 1078-0432; 1557-3265

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 × 10 4 MBT-2 cells implanted orthotopically on day 0. Multiple vaccination schedules were performed with i.p. injection of 5 × 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.