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.