Selective targeting of up-regulated
integrins on
tumor cells is a novel antiangiogenesis strategy for treating solid
tumors.
CNTO 95 is a fully human anti-
alpha(v) integrin monoclonal antibody and has shown antitumor activity when used as a single agent in preclinical studies. We previously showed that radiation combined with an
integrin alpha(v)beta(3) antagonist
cRGD peptide increased the therapeutic efficacy of radiation in preclinical
tumor models. We hypothesized that the combination of radiation and
CNTO 95 would synergistically enhance the efficacy of
radiation therapy. The in vitro studies showed that
CNTO 95 radiosensitized and induced apoptosis in M21 cells in
vitronectin-coated dishes. In mice bearing established human
cancer xenograft
tumors,
CNTO 95 alone had only a moderate effect on
tumor growth. The combined
therapy of
CNTO 95 and fractionated radiation significantly inhibited
tumor growth and produced the longer
tumor growth delay time in multiple
tumor models. Maintenance dosing of
CNTO 95 following irradiation contributed to efficacy and was important for continued inhibition of
tumor regrowth. Immunohistochemistry studies showed that the combined use of
CNTO 95 and radiation reduced the
alpha(v) integrin and
vascular endothelial growth factor receptor expression and the microvessel density and increased apoptosis in
tumor cells and the tumor microenvironment.
CNTO 95 alone and in combination with radiation did not produce any obvious signs of systemic toxicity. These results show that
CNTO 95 can potentiate the efficacy of fractionated
radiation therapy in a variety of human
cancer xenograft
tumor types in nude mice. These findings are very promising and may have high translational relevance for the treatment of patients with solid
tumors.