Potent activity of soluble B7-IgG fusion proteins in therapy of established tumors and as vaccine adjuvant

• Published in: Cancer research (Chicago, Ill.) Ill.), 1999-10, Vol.59 (19), p.4964-4972
• Main Authors: STURMHOEFEL, K, KWANG LEE, GRAY, G. S, THOMAS, J, ZOLLNER, R, O'TOOLE, M, SWINIARSKI, H, DORNER, A, WOLF, S. F
• Format: Article
• Language: English
• Subjects: AB7 antigen; Adjuvants, Immunologic - therapeutic use; AIDS/HIV; Animals; Antineoplastic agents; Biological and medical sciences; Cancer Vaccines - therapeutic use; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Female; Immunoglobulin Fc Fragments - therapeutic use; Immunoglobulin G - therapeutic use; Immunotherapy; Interferon-gamma - deficiency; Interferon-gamma - genetics; Interferon-gamma - physiology; Lymphocyte Depletion; Medical sciences; Melanoma, Experimental - immunology; Melanoma, Experimental - therapy; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Knockout; Pharmacology. Drug treatments; Recombinant Fusion Proteins - therapeutic use; Sarcoma, Experimental - immunology; Sarcoma, Experimental - therapy; Urinary Bladder Neoplasms - immunology; Urinary Bladder Neoplasms - therapy
• ISSN: 0008-5472; 1538-7445

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.