Abstract C138: Anti-αv integrin monoclonal antibody intetumumab (CNTO 95) enhances the therapeutic efficacy of radiation therapy and reduces metastasis of human cancer xenografts in nude rats
Authors: Ning Shoucheng , Marshall Deborah J. , Knox Susan J. 
Published: June 2012

Radiation therapy is used to treat cancer in over 50% of all cancer patients. Interaction of tumor cells with the extracellular matrix via adhesion molecules is important for survival of cancer stem cells, and may play a role in resistance to radiation therapy. Preclinical and clinical studies from our lab and others have demonstrated that a fully human anti- v integrin monoclonal antibody intetumumab (CNTO 95) may enhance the therapeutic index of radiotherapy by selective targeting of upregulated integrins on tumor cells and vascular endothelial cells of tumors. We previously reported that intetumumab is a radiosensitizer in mice with xenograft tumors. However, since intetumumab does not cross-react with mouse integrins, but has limited cross-reactivity with rat integrins, we next studied the potential of combined use of fractionated local tumor radiation therapy and intetumumab in human cancer xenograft models in nude rats in order to assess effects on both tumor cells and vasculatures. We found that intetumumab alone had a moderate effect on tumor growth in human head and neck cancer and non-small cell lung cancer xenograft models. When combined with fractionated radiation therapy, intetumumab significantly inhibited tumor growth and produced a tumor response rate that was significantly better than with radiation therapy alone (P &lt; 0.01). The total tumor response rate (complete response and partial response) was 67% in A549 NSCLC model for intetumumab plus radiotherapy compared with 17% for radiotherapy alone. Treatment with intetumumab reduces the lung metastasis by inhibiting the homing of A549 NSCLC cells, as well as spontaneous metastasis to lung from subcutaneous tumors in A549 NSCLC xenograft model. The blood perfusion and blood volume in xenograft tumors measured by micro-bubble enhanced ultrasound image was substantially improved by treatment of intetumumab. Immunohistochemistry staining of xenograft tumor sections demonstrated that the combined use of intetumumab and radiation therapy significantly reduced the microvessel density and increased apoptosis in tumor cells and the tumor microenvironment. The oxygenation and hypoxic status of tumors treated with intetumumab with or without radiotherapy is under investigation and will be presented. Furthermore, intetumumab alone and in combination with radiation was well-tolerated and did not produce any obvious signs of systemic toxicity. An in vivo toxicity study of crypt stem cell survival in the gastrointestinal tract demonstrated that treatment with intetumumab did not alter the number of surviving crypt stem cells of duodenum, jejunum, or ileum following irradiation, suggesting that intetumumab did not sensitize the sensitive GI epithelium to the effect of radiation therapy. These results demonstrate that intetumumab can potentiate the efficacy of fractionated radiation therapy in human cancer xenograft tumors in nude rats. These findings are promising and may have high translational relevance for the treatment of patients with solid tumors.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C138.