Anti-integrin monoclonal antibody CNTO 95 enhances the therapeutic efficacy of fractionated radiation therapy in vivo

Abstract

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-A 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 A v B 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 A 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. [Mol Cancer Ther 2008;7(6):1569 -78]

Integrin β1-dependent invasive migration of irradiation-tolerant human lung adenocarcinoma cells in 3D collagen matrix

“…It is also reported that a combined therapy of CNTO 95, the anti-human integrin αv monoclonal antibody and fractionated radiation is more effective than radiation therapy only [15]. Moreover, integrin β1 plays an essential role in mediating post-radiation cancer cell survival [16].…”

Anti–αv Integrin Monoclonal Antibody Intetumumab Enhances the Efficacy of Radiation Therapy and Reduces Metastasis of Human Cancer Xenografts in Nude Rats

“…Intetumumab has been reported to inhibit cell adhesion, migration, invasion, and proliferation of endothelial cells and tumor cells in vitro and tumor metastasis in vivo in nude mice with human breast cancer xenografts by inactivating the focal adhesion kinase (FAK) and the docking protein paxillin (1,4). We have previously shown that intetumumab is a potential radiation sensitizer when used in combination with fractionated radiation therapy in human cancer xenograft models in nude mice (5). Data from two multicenter clinical phase I studies in patients with advanced solid tumors have shown that intetumumab was safe and well tolerated either alone or in combination with docetaxel (6,7).…”

Can 111In-RGD2 Monitor Response to Therapy in Head and Neck Tumor Xenografts?

“…This finding could have major implications when planning the treatment schedules of patients for whom both radiotherapy and chemotherapy are used. On the other hand, an increased uptake of 111 In-RGD 2 at day 15 after irradiation could also be explained by an enhanced, though delayed, expression of integrin a v b 3 , as suggested by other in vivo experiments (27,30,31). Nonetheless, the early and late effects of radiation on tumor vascularity, perfusion, and integrin a v b 3 expression require further investigation.…”

“…The sensitivity of the tracer is highlighted in Table 4, where immunohistochemical analysis of integrin b 3 expression remained unaltered after irradiation. Few studies have investigated the expression of integrin a v b 3 after irradiation of tumors; one study also showed that at 3 d after the last radiation fraction, expression of integrin a v b 3 in tumor xenografts was decreased (27). In vitro studies have also previously shown that integrin expression levels on endothelial cells can change within hours after radiotherapy (28,29).…”