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  • Title: Combined therapy of local and metastatic 4T1 breast tumor in mice using SU6668, an inhibitor of angiogenic receptor tyrosine kinases, and the immunostimulator B7.2-IgG fusion protein.
    Author: Huang X, Wong MK, Yi H, Watkins S, Laird AD, Wolf SF, Gorelik E.
    Journal: Cancer Res; 2002 Oct 15; 62(20):5727-35. PubMed ID: 12384531.
    Abstract:
    The therapeutic efficacy of combined antiangiogenic and immune therapy was tested against weakly immunogenic and highly metastatic 4T1 breast tumor using SU6668, an angiogenesis inhibitor and recombinant murine (rm) B7.2-IgG fusion protein, an immunostimulator. SU6668 inhibits the tyrosine kinase activity of three angiogenic receptors VEGFR2 (Flk-1/KDR), PDGFRbeta, and FGFR1, which play a crucial role in tumor-induced vascularization. rmB7.2-IgG is a fusion protein of the extracellular domain of B7.2, and the hinge and constant domains of murine IgG2a. Intermolecule disulfide linkages are maintained so that it forms a dimer. Our studies showed that three weekly immunizations of BALB/c mice bearing 0.5-0.8 cm 4T1 breast tumors with rmB7.2-IgG and irradiated 4T1 tumor cells (B7.2-IgG/TC) resulted in a significant inhibition of tumor growth and formation of pulmonary metastases. T-cell depletion experiments revealed that both CD4(+) and CD8(+) T lymphocytes are required for stimulation of the antitumor and antimetastatic immune response by B7.2-IgG/TC. Treatment of mice with SU6668 substantially inhibited tumor vascularization but did not inhibit tumor infiltration by T lymphocytes or the T-cell response to rmB7.2-IgG therapy. On the contrary, tumors in mice immunized with B7.2-IgG/TC and treated with SU6668 had higher numbers of tumor infiltrating T cells than tumors of other groups. SU6668 treatments initiated either on day 3 or day 10 after inoculation of 4T1 tumor cells resulted in a significant inhibition of tumor growth. Similarly, three weekly immunizations with B7.2-IgG/TC starting either on day 7 or 12 inhibited growth of 4T1 tumors. However, the most potent antitumor effects were observed in mice treated with a combination of SU6668 and B7.2-IgG/TC. Analysis of pulmonary metastases revealed that combined therapy also had a more potent antimetastatic effect than each modality alone. These results indicate that antiangiogenic and immune therapies using SU6668 and B7.2-IgG/TC are compatible, and manifest complementary antitumor and antimetastatic effects. Combined antiangiogenic and immune therapy might represent a new strategy for cancer treatment.
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