title: Potent activity of soluble B7-IgG fusion proteins in therapy of established tumors and as vaccine adjuvant.
abstract: Fusion proteins consisting of the extracellular region of murine B7.1 or B7.2 and the Fc portion of murine IgG2a (B7-IgG) were evaluated for their ability to promote antitumor responses. Therapeutic administration of soluble B7-IgG in mice with established tumors induced complete regression of the tumor and increased the survival of mice. In three models, MethA, P815, and MB49, mice with 7-day-old established tumors were cured with two to three treatment cycles of B7-IgG, given twice a week. Even in mice with an established B16/F10 tumor (a poorly immunogenic melanoma), therapeutic treatment with B7-IgG alone slowed tumor growth and increased survival significantly. Still stronger antitumor activity was achieved when B7-IgG was used as a vaccine adjuvant mixed with irradiated tumor cells. In 80% of mice with 7-day-old B16 tumors, tumors regressed completely, and mice survived for at least 80 days. In all tumor models, B7.1-IgG and B7.2-IgG had similar antitumor activity. B7-IgG-mediated tumor rejection was dependent on T cells, specifically CD8 cells, as demonstrated by the failure of B7-IgG to induce tumor regression in severe combined immunodeficient or CD8-depleted mice. In addition, mice that were cured of an established tumor were protected against a rechallenge with the same tumor for at least 4 months, suggesting the generation of memory responses. Surprisingly, the antitumor activity of B7-IgG was independent of IFN-gamma, as demonstrated by tumor rejection in IFN-gamma knockout mice. Our findings demonstrate the potent capacity of B7-IgG to generate or enhance antitumor immune responses and suggest the clinical value of B7-IgG.
authors.affiliation: Genetics Institute, Andover, Massachusetts 01810, USA. Knut.Sturmhoefel@emindustries.com
authors.forename: K
authors.initials: K
authors.lastname: Sturmhoefel
authors.forename: K
authors.initials: K
authors.lastname: Lee
authors.forename: G S
authors.initials: GS
authors.lastname: Gray
authors.forename: J
authors.initials: J
authors.lastname: Thomas
authors.forename: R
authors.initials: R
authors.lastname: Zollner
authors.forename: M
authors.initials: M
authors.lastname: O'Toole
authors.forename: H
authors.initials: H
authors.lastname: Swiniarski
authors.forename: A
authors.initials: A
authors.lastname: Dorner
authors.forename: S F
authors.initials: SF
authors.lastname: Wolf
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000627:therapeutic use*; D005260:Female; D007141:Immunoglobulin Fc Fragments / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000627:therapeutic use; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008212:Lymphocyte Depletion; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D012513:Sarcoma, Experimental / Q000276:immunology* / Q000628:therapy; D001749:Urinary Bladder Neoplasms / Q000276:immunology* / Q000628:therapy
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma