title: Interferon-alpha gene therapy in combination with CD80 transduction reduces tumorigenicity and growth of established tumor in poorly immunogenic tumor models.
abstract: Interferon-alpha (IFN-alpha) or CD80 transduction of tumor cells individually reduces tumorigenicity and enhances antitumor responses. Here, we report that the combination of IFN-alpha and CD80 cancer gene therapy in poorly immunogenic murine tumor models, the colorectal adenocarcinoma cell line MC38, and the methylcholanthrene-induced fibrosarcoma cell line MCA205 reduces tumor growth more efficiently without affecting in vitro growth. Wild-type (WT), neomycin-resistance (Neo) gene-, or CD80-transduced tumor cells grew progressively in all immunocompetent mice. In contrast, IFN-alpha-transduced MC38 or MCA205 cells were rejected in 13 of 15 and seven of 15 mice, respectively. Synergistic effects were observed when IFN-alpha- and CD80-transduced tumor cells were mixed and inoculated. These admixed cells were rejected by 14 of 15 (MC38) or seven of 15 mice (MCA205), whereas, a mixture of IFN-alpha and Neo cells or CD80 and Neo cells led to tumors associated with progressive growth. Induction of long-lasting tumor immunity against WT tumor cells was demonstrated by rejection of a subsequent rechallenge in 10 of 13 (MC38) and six of seven (MCA205) tumor-free mice. The therapeutic efficacy with established WT MC38 tumors was shown when mice were treated with a vaccine consisting of repetitive injections of IFN-alpha- and CD80-transduced MC38 cells into the contralateral flank (P < 0.01). This treatment was associated with accumulation of CD4+, CD8+ cells and dendritic cells within the established tumor, demonstrating induction of antitumor immune responses. Combination gene therapy using IFN-alpha and CD80 is an effective immune therapy of cancer and could be considered for clinical trials.
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, PA 15261, USA.
authors.forename: K
authors.initials: K
authors.lastname: Hiroishi
authors.forename: T
authors.initials: T
authors.lastname: Tüting
authors.forename: H
authors.initials: H
authors.lastname: Tahara
authors.forename: M T
authors.initials: MT
authors.lastname: Lotze
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage*; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D016233:Immunotherapy, Active / Q000379:methods*; D016219:Immunotherapy, Adoptive; D016898:Interferon-alpha / Q000235:genetics*; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D012190:Retroviridae / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D018122:B7-1 Antigen; D019496:Cancer Vaccines; D016898:Interferon-alpha