Potent activity of soluble B7-IgG fusion proteins in therapy of established tumors and as vaccine adjuvant.
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.
Sturmhoefel
K
K
Genetics Institute, Andover, Massachusetts 01810, USA. Knut.Sturmhoefel@emindustries.com
Lee
K
K
Gray
G S
GS
Thomas
J
J
Zollner
R
R
O'Toole
M
M
Swiniarski
H
H
Dorner
A
A
Wolf
S F
SF
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
D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma