Synergy between an antiangiogenic integrin alpha(v) antagonist and an antibody-cytokine fusion protein eradicates spontaneous tumor metastases

The suppression and eradication of primary tumors and distant metastases is a major goal of alternative treatment strategies for cancer, such as inhib ition of angiogenesis and targeted immunotherapy. We report here a synergy between two novel monotherapies directed against vascular and tumor compart ments, respectively, a tumor vasculature-specific antiangiogenic integrin a lpha(v) antagonist and tumor-specific antibody-interleukin 2 (IL-2) fusion proteins. Simultaneous and sequential combination of these monotherapies ef fectively eradicated spontaneous liver metastases in a poorly immunogenic s yngeneic model of neuroblastoma. This was in contrast to controls subjected to monotherapies with either an antiangiogenic integrin alpha(v) antagonis t or antibody-IL-2 fusion proteins, which were only partially effective at the dose levels applied, Furthermore, simultaneous treatments with the inte grin ct, antagonist and tumor-specific antibody-IL-2 fusion proteins induce d dramatic primary tumor regressions in three syngeneic murine tumor models , i.e., melanoma, colon carcinoma, and neuroblastoma, However, each agent u sed as monotherapy induced only a delay in tumor growth. A mechanism for th is synergism was suggested because the antitumor response was accompanied b y a simultaneous 50% reduction in tumor vessel density and a 5-fold increas e in inflammatory cells in the tumor microenvironment, Subsequently, tumor necrosis was demonstrated only in animals receiving the combination therapy , but not when each agent,vas applied as monotherapy. The results suggest t hat these synergistic treatment modalities may provide a novel and effectiv e tool for future therapies of metastatic cancer.