Immune response against 3LL Lewis lung carcinoma potentiates the therapeutic efficacy of endostatin

The ability of the antitumor immune response to potentiate the therapeutic efficacy of the antiangiogenic agent endostatin was investigated. The antit umor effects of endostatin were tested against weakly immunogenic 3LL Lewis lung carcinoma and its highly immunogenic variant 3LL-C75. Using in vivo M atrigel assay, it was found that the recombinant endostatin produced in the authors' laboratory has a potent antiangiogenic effect. Endostatin manifes ted 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 reg ression were found in mice bearing weakly immunogenic 3LL tumor. 3LL and 3L L-C75 cells produced similar amounts of Vascular Endothelial Growth Factor, and immunohistochemical analysis revealed that endostatin treatment reduce d 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 resu lts suggest that the host's immune response may potentiate the antitumor ef fects of antiangiogenic agents. This possibility was further supported by f indings that the antitumor activity of endostatin against 3LL-C75 tumor was lower in immunodeficient than in immunocompetent mice. Stimulation of immu ne response against 3LL tumor by vaccination with highly immunogenic 3LL-C7 5 cells substantially increased the antitumor effect of endostatain, result ing in a complete and permanent regression of 3LL tumor in 50% of mice. Tum or vaccination or endostatin treatment applied separately inhibited but did not induce regression of 3LL tumor. These results suggest that the combine d attack against tumor cells and the tumor vascular system using antitumor immune mechanisms and antiangiogenic drugs can be a promising strategy for cancer treatment.