Enhancement of radiation therapy by tumor necrosis factor alpha in human colon cancer using a bispecific antibody.

Abstract

To overcome the systemic side effects of tumor necrosis factor alpha (TNFalpha) injected i.v., we used a bispecific antibody (BAb) directed against carcinoembryonic antigen (CEA) and TNFalpha to target this cytokine in human CEA-expressing colorectal carcinoma treated simultaneously with radiation therapy (RT). LS174T cell line was used to study the interaction of TNFalpha and radiation on clonogenic cytotoxicity. When TNFalpha (2500 U/mL) was added 12 h before RT, the surviving fraction at 2 Gy was 54% lower than that obtained with irradiation alone (0.23 vs. 0.42, respectively, p = 0.001). At 20%, 50%, or 70% survival, data points were within the envelope of additivity. Concerning in vivo experiments, RT as a single agent slowed tumor progression as compared with the control group (p = 0.027), whereas TNFalpha, BAb, or BAb + TNFalpha had no effect. BAb + TNFalpha + RT combination enhanced the delay for the tumor to reach 2000 mm(3) as compared with RT alone (p = 0.033, for BAb + TNFalpha + RT group vs. RT group). These results suggest that TNFalpha in combination with BAb and RT may be beneficial for the treatment of locally advanced colorectal cancer.