The ability of the antitumor immune response to potentiate the therapeutic efficacy of the
antiangiogenic agent endostatin was investigated. The antitumor effects of
endostatin were tested against weakly immunogenic 3LL
Lewis lung carcinoma and its highly immunogenic variant 3LL-C75. Using in vivo
Matrigel assay, it was found that the recombinant
endostatin produced in the authors' laboratory has a potent antiangiogenic effect.
Endostatin manifested a more potent antitumor effect against highly immunogenic 3LL-C75 than weakly immunogenic 3LL
tumor.
Endostatin induced regression of immunogenic 3LL-C75
tumor in 40% of C57BL/6 mice, whereas partial inhibition and no regression were found in mice bearing weakly immunogenic 3LL
tumor. 3LL and 3LL-C75 cells produced similar amounts of
Vascular Endothelial Growth Factor, and immunohistochemical analysis revealed that
endostatin treatment reduced microvessel density in both 3LL and 3LL-C75
tumors. However, infiltration of T lymphocytes was observed in 3LL-C75 but not in 3LL
tumors. These results suggest that the host's immune response may potentiate the antitumor effects of
antiangiogenic agents. This possibility was further supported by findings that the antitumor activity of
endostatin against 3LL-C75
tumor was lower in immunodeficient than in immunocompetent mice. Stimulation of immune response against 3LL
tumor by vaccination with highly immunogenic 3LL-C75 cells substantially increased the antitumor effect of endostatain, resulting in a complete and permanent regression of 3LL
tumor in 50% of mice.
Tumor vaccination or
endostatin treatment applied separately inhibited but did not induce regression of 3LL
tumor. These results suggest that the combined attack against
tumor cells and the
tumor vascular system using antitumor immune mechanisms and antiangiogenic drugs can be a promising strategy for
cancer treatment.