Combination B7-Fc Fusion Protein Treatment and Treg Cell Depletion Therapy

• Published in: Clinical cancer research 2005-12, Vol.11 (23), p.8492-8502
• Main Authors: Liu, Aihong, Hu, Peisheng, Khawli, Leslie A, Epstein, Alan L
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; B7-1 Antigen - genetics; B7-1 Antigen - immunology; B7-1 Antigen - metabolism; B7.1-Fc; B7.2-Fc; Biological and medical sciences; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - immunology; Carcinoma, Renal Cell - therapy; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Cell Proliferation; Colonic Neoplasms - genetics; Colonic Neoplasms - immunology; Colonic Neoplasms - therapy; Costimulation; Disease Models, Animal; Female; Genetic Vectors - genetics; Humans; Immunoglobulin Fc Fragments - genetics; Immunoglobulin Fc Fragments - immunology; Immunoglobulin Fc Fragments - metabolism; Immunoglobulin G - genetics; Immunoglobulin G - immunology; Immunoglobulin G - metabolism; Interferon-gamma - genetics; Interferon-gamma - physiology; Kidney Neoplasms - genetics; Kidney Neoplasms - immunology; Kidney Neoplasms - therapy; Lymph Nodes - immunology; Lymph Nodes - pathology; Lymphocyte Depletion; Lymphocytes, Tumor-Infiltrating; Medical sciences; Membrane Glycoproteins - genetics; Membrane Glycoproteins - physiology; Mice; Mice, Inbred BALB C; Mice, Knockout; Necrosis; Perforin; Pharmacology. Drug treatments; Pore Forming Cytotoxic Proteins; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - immunology; Recombinant Fusion Proteins - metabolism; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Treg cells; Tumor immunotherapy
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-1411

Purpose: A B7.1 fusion protein consisting of the extracellular domains of human B7.1 and the Fc portion of human IgG1, called B7.1-Fc, was generated and evaluated for its antitumor potential when used alone or in combination with regulatory T (Treg) cell depletion. Methods: A human B7.1-Fc fusion protein was constructed, expressed, purified, and examined for its antitumor activity in experimental mouse tumor models. Results: Soluble B7.1-Fc showed costimulatory activity of T-cell proliferation in vitro , and when given in vivo , it induced complete regression of Colon 26 tumors after a 5-day treatment regimen. Parallel studies with human B7.2-Fc gave very similar results in the Colon 26 tumor model. Even in mice with established RENCA and Madison 109 tumors, which are poorly immunogenic, B7.1-Fc treatment slowed tumor growth dramatically. In these models, more potent antitumor activity was achieved when B7.1-Fc was used in combination with Treg depletion by i.p. administration of antibody PC61. Rechallenge experiments done with mice that had sustained complete tumor regressions showed that these mice had immunologic memory by their ability to reject subsequent implants. Histologically, B7.1-Fc treatment induced multiple areas of necrosis and infiltration of CD4 + and CD8 + T cells in tumors along with a concomitant dramatic increase in T-cell proliferation in tumor-draining lymph nodes. Conclusions: The B7.1-Fc fusion protein seems to be an effective antitumor agent especially in combination with Treg depletion. Its potency in stimulating immune responses and its human origin suggest that clinical studies may be warranted in the future.